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Cheungpasitporn W, Krisanapan P, Suppadungsuk S, Thongprayoon C, Fülöp T, Miao J, Soliman KM, Ho YS. Research trends and performance of endothelin A receptor antagonist in kidney care: a bibliometric analysis. Ren Fail 2025; 47:2487212. [PMID: 40211733 PMCID: PMC11995767 DOI: 10.1080/0886022x.2025.2487212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 03/11/2025] [Accepted: 03/22/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Endothelin A receptor antagonists (ERAs) have emerged as pivotal therapeutic agents in managing pulmonary hypertension (PH) and various kidney disorders, including chronic kidney disease (CKD) and proteinuric glomerular diseases such as IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS). Although initially developed for pulmonary applications, recent research has highlighted their renoprotective effects, expanding their role in nephrology. This study presents a comprehensive bibliometric analysis of global research trends, key contributors, and emerging applications of ERAs in kidney care over the past three decades. METHODS A bibliometric analysis was performed using the Science Citation Index Expanded database (1992-2023). Relevant kidney-related publications were identified through specific keyword searches. Author performance was assessed using the Y-index. RESULTS ERA-related research has shown significant growth, particularly in nephrology. The United States and the University of Groningen lead in publication volume and international collaborations, with H.J.L. Heerspink emerging as a key contributor. While PH remains the dominant research focus, nephrology applications are rapidly increasing, particularly in CKD, diabetic nephropathy (DN), and glomerular diseases. A major milestone was the accelerated FDA approval of sparsentan for IgAN in 2023, followed by full approval in 2024 based on confirmatory efficacy data. However, challenges such as fluid retention and cardiovascular risks remain, necessitating further investigation into optimized ERA therapies, including combination strategies with SGLT2 inhibitors. CONCLUSIONS The expanding role of ERAs in nephrology underscores their potential in treating proteinuric kidney diseases. Ongoing international collaborations are advancing research on ERA safety, efficacy, and novel therapeutic strategies, supporting their broader clinical application.
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Affiliation(s)
| | - Pajaree Krisanapan
- Department of Medicine, Division of Nephrology, Mayo Clinic, Rochester, MN, USA
- Department of Nephrology, Department of Internal Medicine, Thammasat University, Khlong Nueng, Thailand
| | - Supawadee Suppadungsuk
- Department of Medicine, Division of Nephrology, Mayo Clinic, Rochester, MN, USA
- Faculty of Medicine Ramathibodi Hospital, Chakri Naruebodindra Medical Institute, Bang Pla, Thailand
| | - Charat Thongprayoon
- Department of Medicine, Division of Nephrology, Mayo Clinic, Rochester, MN, USA
| | - Tibor Fülöp
- Medical Services, Ralph H. Johnson VA Medical Center, Charleston, SC, USA
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA
| | - Jing Miao
- Department of Medicine, Division of Nephrology, Mayo Clinic, Rochester, MN, USA
| | - Karim M. Soliman
- Medical Services, Ralph H. Johnson VA Medical Center, Charleston, SC, USA
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA
| | - Yuh-Shan Ho
- Trend Research Centre, Asia University, Taichung, Taiwan
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Ma X, Liang Y, Chen W, Zheng L, Lin H, Zhou T. The role of endothelin receptor antagonists in kidney disease. Ren Fail 2025; 47:2465810. [PMID: 40015728 PMCID: PMC11869344 DOI: 10.1080/0886022x.2025.2465810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 03/01/2025] Open
Abstract
Kidney diseases are among the most prevalent conditions worldwide, impacting over 850 million individuals. They are categorized into acute kidney injury and chronic kidney disease. Current preclinical and clinical trials have demonstrated that endothelin (ET) is linked to the onset and progression of kidney disease. In kidney diseases, pathological conditions such as hyperglycemia, acidosis, insulin resistance, and elevated angiotensin II levels lead to an increase in ET. This elevation activates endothelin receptor type A, resulting in harmful effects like proteinuria and a reduced glomerular filtration rate (GFR). Therefore, to slow the progression of kidney disease, endothelin receptor antagonists (ERAs) have been proposed as promising new therapies. Numerous studies have demonstrated the efficacy of ERAs in significantly reducing proteinuria and improving GFR, thereby slowing the progression of kidney diseases. This review discusses the mechanisms of action of ERAs in treating kidney disease, their efficacy and safety in preclinical and clinical studies, and explores future prospects for ERAs.
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Affiliation(s)
- Xiaoting Ma
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Yuyang Liang
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Wenmin Chen
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Lingqian Zheng
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Haishan Lin
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Tianbiao Zhou
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
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Law KC, Quattrocchi AT, Xuereb BE, Moriarty N, Thompson LH, Parish CL. A pharmacological vasoconstrictor cocktail targeting endothelin signalling generates a stable, reproducible focal cerebral infarct with associated functional deficits in mice. Exp Neurol 2025; 388:115215. [PMID: 40081787 DOI: 10.1016/j.expneurol.2025.115215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 02/28/2025] [Accepted: 03/09/2025] [Indexed: 03/16/2025]
Abstract
Necessary for enhanced understanding of brain injury, and for developing new therapies, is the generation of reliable animal models. While many models are available, each comes with benefits and limitations. Intracerebral injection of the vasoconstrictive peptide endothelin-1 creates one of the most widely adopted models of focal ischemic stroke in rats, yet its potency is underwhelming in mice. This is likely underpinned by the greater proportions of vasodilatory compared to vasoconstrictive receptor subtypes in the mouse brain. Yet mouse models of ischemic stroke provide the benefit of exploiting the wide range of transgenic strains that can aid in further understanding pathophysiology mechanisms of acute and secondary damage, as well as endogenous recovery. To improve the efficiency of focal endothelin-1 infarcts in mice, we investigated the impact of co-administering pharmacological compounds that target endothelin receptor subtypes and downstream signalling, aimed at selectively enhancing vasoconstriction whilst reducing vasodilation. We report exacerbated neuronal loss and tissue atrophy resulting in motor and cognitive dysfunction when endothelin-1 was co-administered with the nitric oxide synthase inhibitor L-NAME and the selective ETB1 antagonist RES-701-1. These infarcts were stable, reproducible and achievable across brain regions. These findings demonstrate a new and effective mouse model to study focal ischemic stroke.
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Affiliation(s)
- Kevin Cl Law
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, Australia
| | - Andrew T Quattrocchi
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
| | - Brianna E Xuereb
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
| | - Niamh Moriarty
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
| | - Lachlan H Thompson
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, Australia
| | - Clare L Parish
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia.
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4
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Dubey N, Verma A, Goyal A, Vishwakarma V, Bhatiya J, Arya DS, Yadav HN. The role of endothelin and its receptors in cardiomyopathy: From molecular mechanisms to therapeutic insights. Pathol Res Pract 2025; 269:155932. [PMID: 40174273 DOI: 10.1016/j.prp.2025.155932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 03/17/2025] [Accepted: 03/26/2025] [Indexed: 04/04/2025]
Abstract
Cardiomyopathy is an anatomical and pathologic condition that is related to the cardiac muscle or left ventricular failure. A diverse range of illnesses known as cardiomyopathies often result in progressive heart failure with high morbidity and death rates. Primary cardiomyopathies are hereditary, mixed, or adopted. Secondary cardiomyopathies are infiltrative, harmful, or pathogenic. The activation of many paracrine, autocrine, and neuroendocrine factors is closely linked to pathological left ventricular (LV) deformation. After the myocardial injury, in the context of higher LV wall pressure and haemodynamic disturbance, these variables are raised. New therapy techniques have been focused on these novel targets after recent studies revealed that endothelin, nitric oxide or cytokines may be implicated in the remodelling process. Vasoconstrictive peptide endothelin-1 (ET-1) is mostly generated in the endothelium and works by binding to the ETA- and ETB-endothelin receptors (ET-Rs). The expression of both ET-Rs is widespread in cardiac tissues. Heart failure, pulmonary arterial hypertension, hypertension, cardiomyopathy, and coronary artery disease are just a few of the cardiovascular disorders for which the endothelin system has been shown to play a crucial role over the years. The occurrence, pathogenesis, and natural history of endothelin antagonists in cardiomyopathies are currently not well understood, and specific aspects of their treatment responses have not received comprehensive attention. Therefore, in this study, we address the variable degrees of success that have been achieved in treating cardiomyopathy using endothelin-targeting treatments, such as endothelin receptor antagonists.
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Affiliation(s)
- Nandini Dubey
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Aanchal Verma
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - Vishal Vishwakarma
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Jagriti Bhatiya
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Dharamvir Singh Arya
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Harlokesh Narayan Yadav
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.
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Dunaway L, Mills W, Eyo U, Isakson B. The Cells of the Vasculature: Advances in the Regulation of Vascular Tone in the Brain and Periphery. Basic Clin Pharmacol Toxicol 2025; 136:e70023. [PMID: 40143606 PMCID: PMC11947641 DOI: 10.1111/bcpt.70023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/20/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025]
Abstract
The vasculature is a complex tissue in which multiple cell types coordinate the regulation of tissue perfusion in response to hemodynamic and biochemical signals. Advances in this field are continuing to deepen our understanding of the relative importance of these cell types through the body. In the peripheral vasculature, tone is generated primarily by smooth muscle cells and regulated by endothelial cells, and neurons. In the brain parenchyma, unique cell types including pericytes, perivascular astrocytes and microglia, also contribute to the regulation of arterial and capillary tone. Here, we provide a cell-by-cell review of the regulation of vascular tone and highlight recent advances in the regulation of vascular tone in both the periphery and cerebral vasculature.
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Affiliation(s)
- Luke S. Dunaway
- Robert M. Berne Cardiovascular Research CenterUniversity of Virginia School of MedicineCharlottesvilleVirginiaUSA
| | - William A. Mills
- Robert M. Berne Cardiovascular Research CenterUniversity of Virginia School of MedicineCharlottesvilleVirginiaUSA
- Brain Immunology & Glia Center, Department of NeuroscienceUniversity of Virginia School of MedicineCharlottesvilleVirginiaUSA
- Brain InstituteUniversity of Virginia School of MedicineCharlottesvilleVirginiaUSA
| | - Ukpong B. Eyo
- Robert M. Berne Cardiovascular Research CenterUniversity of Virginia School of MedicineCharlottesvilleVirginiaUSA
- Brain Immunology & Glia Center, Department of NeuroscienceUniversity of Virginia School of MedicineCharlottesvilleVirginiaUSA
| | - Brant E. Isakson
- Robert M. Berne Cardiovascular Research CenterUniversity of Virginia School of MedicineCharlottesvilleVirginiaUSA
- Department of Molecular Physiology and BiophysicsUniversity of Virginia School of MedicineCharlottesvilleVirginiaUSA
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6
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Tran NKC, Jeong JH, Sharma N, Nguyen YND, Park JH, Nguyen KNT, Tran HYP, Dang DK, Kim HC, Shin EJ. Neuroinflammation Involving Endothelin-1 and Platelet-Activating Factor Receptors Contributes To Self-Injurious Behaviors Induced by Bay k-8644 in Adolescent Mice. Neurochem Res 2025; 50:141. [PMID: 40220052 DOI: 10.1007/s11064-025-04387-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 03/25/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025]
Abstract
Bay k-8644, an activator of L-type voltage-gated calcium channels, induces self-injurious behaviors in mice. Although previous studies using animal models have suggested the possible implications of neuroinflammation in self-injurious behaviors, this has not yet been elucidated in the context of Bay k-8644-induced self-injurious behaviors. In this study, Bay k-8644 (50 µg, i.c.v.)-induced self-injurious behaviors were accompanied by increased expression of endothelin (ET)-1, platelet-activating factor (PAF) receptors, and Iba-1 in the striatum. Pretreatment with the ET receptor antagonist bosentan (10 mg/kg, i.p.), the PAF receptor antagonist ginkgolide B (10 mg/kg, i.p.), or the microglial activation inhibitor minocycline (40 mg/kg/day for 5 days, i.p.) significantly inhibited Bay k-8644-induced self-injurious behaviors and microglial activation in the striatum. Interestingly, bosentan also suppressed Bay k-8644-induced PAF receptor expression, indicating that ET-1 may act as an upstream modulator of the PAF signaling under these experimental conditions. Bay k-8644-induced ET-1 expression and consequent pro-inflammatory changes were reversed by the protein kinase C (PKC) inhibitor NPC-15,437 and the Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor KN-93. Moreover, Bay k-8644-induced self-injurious behaviors and microglial activation were significantly potentiated by exogenous ET-1 administration (10 pmol, i.c.v.) or by weak neuroinflammation in the striatum induced by systemic injection of low-dose lipopolysaccharide (LPS; 1 mg/kg, i.p.). Our results suggest that neuroinflammatory changes associated with ET-1/PAF signaling in the striatum contribute to Bay k-8644-induced self-injurious behaviors.
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Affiliation(s)
- Ngoc Kim Cuong Tran
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea
| | - Ji Hoon Jeong
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, College of Medicine, Chung-Ang University, Seoul, 06974, Republic of Korea.
| | - Naveen Sharma
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, College of Medicine, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Yen Nhi Doan Nguyen
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea
| | - Jung Hoon Park
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea
| | - Khanh Ngan Thi Nguyen
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea
| | - Hoang-Yen Phi Tran
- Physical Chemistry Department, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, 760000, Viet Nam
| | - Duy-Khanh Dang
- Pharmacy Faculty, Can Tho University of Medicine and Pharmacy, Can Tho City, 900000, Viet Nam
| | - Hyoung-Chun Kim
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, College of Medicine, Chung-Ang University, Seoul, 06974, Republic of Korea.
| | - Eun-Joo Shin
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.
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7
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Severino P, D'Amato A, Prosperi S, Myftari V, Germanò R, Marek-Iannucci S, De Prisco A, Mariani MV, Marchiori L, Battaglia C, Tabacco L, Segato C, Mancone M, Fedele F, Vizza CD. Coronary microcirculation in myocardial ischemia: A genetic perspective. J Mol Cell Cardiol 2025:S0022-2828(25)00060-4. [PMID: 40220989 DOI: 10.1016/j.yjmcc.2025.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 04/06/2025] [Accepted: 04/07/2025] [Indexed: 04/14/2025]
Abstract
Coronary microvascular dysfunction (CMD) is a major contributor to ischemic heart disease (IHD), acting both independently and together with atherosclerosis. CMD encompasses structural and functional microcirculatory changes that result in dysregulated coronary blood flow. Structural abnormalities include microvascular remodeling, resulting in arteriolar and capillary narrowing, perivascular fibrosis and capillary rarefaction. Endothelial dysfunction and smooth muscle cell hyperactivity further impair microcirculation. Genetic factors may play a crucial role in the pathophysiology of CMD, mainly due to single nucleotide polymorphisms (SNPs) in genes that regulate coronary blood flow and microcirculation structural modifications. This manuscript aims to review the genetic determinants of CMD, with particular focus on ion channels, microRNAs (miRNAs), and proteins involved in the endothelial environment. The improving knowledge about genetic aspects of CMD opens the possibility to have new biomarkers, improving diagnosis and the development of targeted treatments in light of an even more patient-tailored approach.
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Affiliation(s)
- Paolo Severino
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Andrea D'Amato
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Silvia Prosperi
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Vincenzo Myftari
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Rosanna Germanò
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Stefanie Marek-Iannucci
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Andrea De Prisco
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Marco Valerio Mariani
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Ludovica Marchiori
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Corinne Battaglia
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Leonardo Tabacco
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Camilla Segato
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Massimo Mancone
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | | | - Carmine Dario Vizza
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
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Sato H, Nagano T, Suraya R, Hazama D, Umezawa K, Katsurada N, Yamamoto M, Tachihara M, Nishimura Y, Emoto N, Kobayashi K. Reduction in circulating Endothelin-1 levels by inhaled COPD medications. Respir Med 2025; 240:108027. [PMID: 40043918 DOI: 10.1016/j.rmed.2025.108027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 02/12/2025] [Accepted: 03/03/2025] [Indexed: 03/09/2025]
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) can be complicated by pulmonary hypertension (PH), impacting prognosis and quality of life. Endothelin-1 (ET-1) is implicated in PH development and elevated in COPD patients. The impact of COPD treatments on ET-1 and COPD-related PH remains unclear. This study investigated changes in ET-1 levels after administration of inhaled COPD medications and explored underlying mechanisms. METHODS Patients underwent pulmonary function tests, COPD Assessment Test, and plasma ET-1 measurement before and 4-12 weeks after treatment initiation. In mice, elastase-induced emphysema was treated with budesonide (BUD), glycopyrronium (GLY), and formoterol (FOR) combinations for 2 weeks. Plasma ET-1 concentration and cytokine expression were analysed. HULEC-5a cells were used to examine ET-1 expression after TNFα stimulation. RESULTS The study included 33 patients. COPD patients (n = 24) showed higher baseline plasma ET-1 levels compared to controls (n = 9) (2.12 pg/ml vs 1.54 pg/ml, p < 0.001). Plasma ET-1 levels decreased in COPD patients posttreatment (2.12-1.82 pg/ml, p = 0.004), with reductions observed across all disease stages and treatment regimens. Mice showed elevated ET-1 levels and expression of inflammatory cytokines after elastase instillation. BUD/GLY/FOR treatment significantly reduced ET-1 concentration and TNFα expression. Furthermore, TNFα stimulation upregulated ET-1 expression in HULEC-5a cells. CONCLUSIONS In COPD patients conventional treatment decreased ET-1 concentration. In mouse models TNFα expression was suppressed by BUD/GLY/FOR. In HULEC-5a cells, TNFα stimulation exerted an increased ET-1expression. These findings suggest that the suppressive effect of inhaler therapy on ET-1 expression is due to the anti-inflammatory effects of these drugs.
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Affiliation(s)
- Hiroki Sato
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Tatsuya Nagano
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
| | - Ratoe Suraya
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Daisuke Hazama
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Kanoko Umezawa
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Naoko Katsurada
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Masatsugu Yamamoto
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Motoko Tachihara
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Yoshihiro Nishimura
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Noriaki Emoto
- Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe, 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe, 6500017, Japan
| | - Kazuyuki Kobayashi
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
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9
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Heerspink HJ, Du X, Xu Y, Zhang Y, Liu B, Bi G, Xu C, Luo Q, Wu H, Wan J, Cao L, Wang R, Fan Q, Cheng H, Xu L, Huang J, Zhong A, Peng Q, Hei Y, Wang Y, Zhou B, Zhang L, Chen J. The Selective Endothelin Receptor Antagonist SC0062 in IgA Nephropathy: A Randomized Double-Blind Placebo-Controlled Clinical Trial. J Am Soc Nephrol 2025; 36:657-667. [PMID: 39462310 PMCID: PMC11975243 DOI: 10.1681/asn.0000000538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 10/09/2024] [Indexed: 10/29/2024] Open
Abstract
Key Points Patients with IgA nephropathy and significant proteinuria are at high risk of progressive kidney function loss and kidney failure. We report the results of a clinical trial assessing the selective endothelin receptor antagonist SC0062 for the treatment of IgA nephropathy. SC0062 led to clinically meaningful improvements in proteinuria and did not increase risk of peripheral edema at higher doses. Background Endothelin receptor type A activation contributes to kidney injury in patients with IgA nephropathy. SC0062 is a novel selective endothelin receptor type A antagonist. We report the results of a phase 2 dose-finding trial to characterize the efficacy and safety of SC0062 in patients with IgA nephropathy. Methods We conducted a randomized, placebo-controlled, double-blind, clinical trial in adults with biopsy-proven IgA nephropathy and eGFR ≥30 ml/min per 1.73 m2 with urine protein-creatinine ratio (UPCR) ≥0.75 g/g or proteinuria ≥1 g/24 hour despite using maximum tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were randomized 1:1:1:1 to 24-week treatment with SC0062 5, 10, and 20 mg or matching placebo once daily. The primary efficacy outcome was percent change from baseline in UPCR in 24-hour urine samples after 12 weeks of treatment. Secondary end points included changes in eGFR. Safety outcomes including treatment-emergent adverse events and serious adverse events were recorded. Results Overall, 131 patients (mean age 42 years [SD 11]; mean eGFR 72 ml/min per 1.73 m2 [SD 24] and median 24-hour UPCR 1.2 g/g [25th–75th percentile, 0.9–1.5 g/g]) were randomized to placebo (n =34) or SC0062 5 mg (n =33), 10 mg (n =32), or 20 mg (n =32). All SC0062 doses reduced UPCR versus placebo throughout treatment. At week 12, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UPCR with SC0062 5, 10, and 20 mg were−27.6% (−43.0 to −8.2), −20.5% (−37.4 to 1.0), and −38.1% (−51.4 to −21.0), respectively, and at week 24 they were−22.4% (−42.2 to 4.3), −30.9% (−48.6 to −7.0), and −51.6% (−64.2 to −34.6), respectively. No differences in eGFR were observed among treatment groups. The proportion of participants with treatment-emergent adverse events or serious adverse events was balanced among treatment groups. Peripheral edema was reported by two (6%), one (3%), one (3%) participants in the 5, 10, and 20 mg SC0062-treated groups, respectively, compared with five (15%) in the placebo group. Conclusions In patients with IgA nephropathy, SC0062 reduced proteinuria and did not increase risk of peripheral edema. Clinical Trial registry name and registration number: A Study to Evaluate the Efficacy and Safety of SC0062 in the Treatment of CKD, NCT05687890 . Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_10_26_KTS_October2024.mp3
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Affiliation(s)
- Hiddo J.L. Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- The George Institute for Global Health, Sydney, New South Wales, Australia
| | - Xiaoying Du
- Kidney Disease Center, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
- National Key Clinical Department of Kidney Diseases, Hangzhou, China
| | - Yan Xu
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanning Zhang
- Department of Nephrology, General Hospital of Northern Theater Command, Shenyang, China
| | - Bin Liu
- Department of Nephrology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Guangyu Bi
- Department of Nephrology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Chengyun Xu
- Department of Nephrology, Nanchang University Second Affiliated Hospital, Nanchang, China
| | - Qun Luo
- Department of Nephrology, Ningbo No. 2 Hospital, Ningbo, China
| | - Henglan Wu
- Department of Nephrology, First Hospital of Jiaxing, Jiaxing, China
| | - Jianxin Wan
- Department of Nephrology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Liou Cao
- Department of Nephrology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qiuling Fan
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Cheng
- Department of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Lixia Xu
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jiyi Huang
- Department of Nephrology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Aimin Zhong
- Department of Nephrology, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Qingfeng Peng
- Department of Nephrology, Zhuzhou Hospital Affiliated to Xiangya Medical College, Central South University, Zhuzhou, China
| | - Yongjiang Hei
- Research and Development Division, Biocity Biopharmaceutics Co., Ltd., Wuxi, China
| | - Yiwei Wang
- Research and Development Division, Biocity Biopharmaceutics Co., Ltd., Wuxi, China
| | - Bo Zhou
- Research and Development Division, Biocity Biopharmaceutics Co., Ltd., Wuxi, China
| | - Liqin Zhang
- Research and Development Division, Biocity Biopharmaceutics Co., Ltd., Wuxi, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
- National Key Clinical Department of Kidney Diseases, Hangzhou, China
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10
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Paul JR, Rhoads MK, Elam A, Pollock DM, Gamble KL. High-Salt Diet Increases Suprachiasmatic Neuronal Excitability Through Endothelin Receptor Type B Signaling. FUNCTION 2025; 6:zqaf014. [PMID: 40042980 PMCID: PMC11940741 DOI: 10.1093/function/zqaf014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 02/12/2025] [Accepted: 03/02/2025] [Indexed: 03/28/2025] Open
Abstract
Circadian rhythms are 24-h oscillations in behavioral and biological processes such as blood pressure and sodium excretion. Endothelin B (ETB) receptor has been connected to the molecular clock in peripheral tissues and plays a key role in the regulation of sodium excretion, especially in response to a high-salt diet. However, little is known about the role of ETB in the primary circadian pacemaker in the brain, the suprachiasmatic nucleus (SCN), despite recent reports showing its enrichment in SCN astrocytes. In this study, we tested the hypothesis that high-salt diet (4.0% NaCl) impacts the circadian system via the ETB receptor at the behavioral, molecular, and physiological levels in C57BL/6 mice. Two weeks of high-salt diet feeding changed the organization of nighttime wheel-running activity, as well as increased the SCN expression of ETB mRNA determined by fluorescence in situ hybridization at night. Neuronal excitability determined using loose-patch electrophysiology was also elevated at night. This high-salt diet-induced increase in SCN activity was ameliorated by ex vivo bath application of an ETB antagonist and could be mimicked with acute treatment of endothelin-3. Finally, we found that the excitatory effects of endothelin-3 were blocked with co-application of an N-methyl-D-aspartate (NMDA) receptor antagonist, suggesting that glutamate mediates endothelin-induced neuronal excitability in the SCN. Together, our data demonstrate the presence of functional ETB receptors in SCN astrocytes and point to a novel role for endothelin signaling in mediating neuronal responses to a dietary sodium intake.
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Affiliation(s)
- Jodi R Paul
- Division of Behavioral Neurobiology, Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA
| | - Megan K Rhoads
- Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35233, USA
| | - Anna Elam
- Division of Behavioral Neurobiology, Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA
| | - David M Pollock
- Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35233, USA
| | - Karen L Gamble
- Division of Behavioral Neurobiology, Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA
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11
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Alhazmi AS. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice. Open Med (Wars) 2025; 20:20251166. [PMID: 40093515 PMCID: PMC11909575 DOI: 10.1515/med-2025-1166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 02/20/2025] [Accepted: 02/20/2025] [Indexed: 03/19/2025] Open
Abstract
Background The Commiphora gileadensis (C. gileadensis) is a tree belonging to the genus Commiphora. Aim of the study: This study investigates the effect of C. gileadensis on erectile dysfunction and infertility in male mice. Methods Fifty male BALB/c mice are divided into five groups: control, untreated diabetic, diabetic C. gileadensis sap-treated, methanol extract-treated, and acetone extract-treated. All groups were assessed for body weight, testicular weight, serum follicle-stimulating hormone, luteinizing hormone, testosterone, prolactin, nitric oxide, adropin, endothelin levels, semen analysis, CD4+, CD8+, CD25+, and testicular nitric oxide synthase (NOS) immunoreactivity. Outcome C. gileadensis maintains sexual integrity and infertility in mice. Results Diabetic groups treated with C. gileadensis had significantly higher body weight than the untreated group. Furthermore, the diabetic group treated with C. gileadensis sap had significantly increased testicular weight than the untreated groups. Diabetic groups treated with C. gileadensis had significantly greater testosterone levels than the untreated groups. Additionally, these groups exhibit considerably higher nitric oxide and adropin levels than the untreated diabetic group. Endothelin levels were considerably lower in diabetic groups treated with C. gileadensis than in the untreated group. Semen analysis shows that the diabetic group treated with C. gileadensis sap had considerably more sperm count than the untreated group (P < 0.05). CD4+, CD8+, CD4+, CD25+, and CD8+ CD25+ were reduced significantly in diabetic mice treated with C. gileadnesis. In addition, the NOS immunoreactivity is greater in diabetic C. gileadensis treated groups than in the untreated group. Clinical implications C. gileadensis induces mice erectile function and fertility. Strength and limitations The study does not use laser Doppler flowmetry for the measurement of erectile dysfunction. Conclusion C. gileadensis ameliorates infertility and erectile dysfunction in diabetic mice.
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Affiliation(s)
- Ayman Saeed Alhazmi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, 24227, 20006 Saudi Arabia
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12
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Okunlola FO, Okunlola AR, Adetuyi BO, Soliman MES, Alexiou A, Papadakis M, Fawzy MN, El-Saber Batiha G. Beyond the gut: Unraveling the multifaceted influence of microbiome on cardiovascular health. Clin Nutr ESPEN 2025; 67:71-89. [PMID: 40064239 DOI: 10.1016/j.clnesp.2025.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 03/02/2025] [Accepted: 03/04/2025] [Indexed: 03/15/2025]
Abstract
Cardiovascular disease is one of the leading causes of death worldwide. Even while receiving adequate pharmacological treatment for their hypertension, people are nonetheless at greater risk for cardiovascular disease. There is growing evidence that the gut microbiota may have major positive and negative effects on blood pressure and illnesses related with it as more study into this topic is conducted. Trimethylamine n-oxide (TMAO) and short-chain fatty acids (SCFA) are two major by-products of the gut microbiota. TMAO is involved in the formation of other coronary artery diseases, including atherosclerosis and hypertension, while SCFAs play an important role in controlling blood pressure. Numerous investigations have confirmed the established link between dietary salt intake and hypertension. Reducing sodium in the diet is linked to lower rates of cardiovascular disease morbidity and mortality as well as lower rates of blood pressure and hypertension. In both human and animal research, high salt diets increase local and systemic tissue inflammation and compromise gut architecture. Given that the gut microbiota constantly interacts with the immune system and is required for the correct maturation of immune cells, it is scientifically conceivable that it mediates the inflammatory response. This review highlights the therapeutic possibilities for focusing on intestinal microbiomes as well as the potential functions of the gut microbiota and its metabolites in the development of hypertension.
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Affiliation(s)
- Felix Oladele Okunlola
- Department of Natural Sciences (Biochemistry Option), Faculty of Pure and Applied Sciences, Precious Cornerstone University, Ibadan, Nigeria.
| | - Abimbola Rafiat Okunlola
- Department of Natural Sciences (Biochemistry Option), Faculty of Pure and Applied Sciences, Precious Cornerstone University, Ibadan, Nigeria.
| | - Babatunde Oluwafemi Adetuyi
- Department of Natural Sciences (Biochemistry Option), Faculty of Pure and Applied Sciences, Precious Cornerstone University, Ibadan, Nigeria.
| | - Mahmoud E S Soliman
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa.
| | - Athanasios Alexiou
- University Centre for Research & Development, Chandigarh University, Chandigarh-Ludhiana Highway, Mohali, Punjab, India; Department of Research & Development, Funogen, Athens, 11741, Greece.
| | - Marios Papadakis
- University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Mohamed N Fawzy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University- Arish Branch, Arish, 45511, Egypt.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira, 22511, Egypt.
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13
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McInnis JJ, LeComte MD, Reed LF, Torsney EE, Del Rio-Guerra R, Poynter ME, Spees JL. Microglial cell proliferation is regulated, in part, by reactive astrocyte ETB R signaling after ischemic stroke. Exp Neurol 2025; 385:115125. [PMID: 39716588 PMCID: PMC11781953 DOI: 10.1016/j.expneurol.2024.115125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 12/01/2024] [Accepted: 12/17/2024] [Indexed: 12/25/2024]
Abstract
Reciprocal communication between reactive astrocytes and microglial cells provides local, coordinated control over critical processes such as neuroinflammation, neuroprotection, and scar formation after CNS injury, but is poorly understood. The vasoactive peptide hormone endothelin (ET) is released and/or secreted by endothelial cells, microglial cells and astrocytes early after ischemic stroke and other forms of brain injury. To better understand glial cell communication after stroke, we sought to identify paracrine effectors produced and secreted downstream of astroglial endothelin receptor B (ETBR) signaling. Using a genetic loss-of-function screen, we identified angiopoietin-2 (Ang-2) as a factor produced by reactive astrocytes in response to ET. In experiments with primary adult astrocytes stimulated by IRL1620, a specific ETBR agonist, we found that ERK1/2 and NFkB mediated the effects of ET on Ang-2 production. To determine astroglial Ang-2 levels in vivo, reactive astrocytes expressing the high affinity glutamate transporter (GLAST, EAAT1) were isolated by magnetic-activated cell sorting 3 days after stroke. Astrocytes obtained from the ipsilateral hemisphere expressed significantly more Ang-2 compared with astrocytes isolated from the contralateral hemisphere, or from cortices of sham-operated (control) mice. Notably, analysis of microglia sorted from CX3CR1-eGFP mice demonstrated increased cell surface expression of Tie-2, the Ang-2 receptor, on cells obtained from ipsilateral versus contralateral tissue. Addition of recombinant Ang-2 to astrocyte-conditioned medium significantly increased the number of SIM-A9 murine microglial cells cultured under hypoxic conditions (1 % oxygen for 48 h). In transgenic GFAP-CreER™-EDNRB-fl/fl mice with stroke, conditional knockout of astroglial ETBR significantly decreased the number of proliferating cells in the peri-infarct area with a microglial phenotype (Ki67+/CD11b+). Our results indicate that Ang-2, and possibly other paracrine effectors functioning downstream of astroglial ETBR signaling, are important mediators of microglial cell dynamics after stroke.
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Affiliation(s)
- John J McInnis
- Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, VT 05446, USA; Department of Neurological Sciences and Neuroscience Graduate Program, University of Vermont, Burlington, VT 05401, USA
| | - Matthew D LeComte
- Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, VT 05446, USA; Department of Neurological Sciences and Neuroscience Graduate Program, University of Vermont, Burlington, VT 05401, USA
| | - Leah F Reed
- Department of Medicine, Pulmonary Disease and Critical Care, University of Vermont, Burlington, VT 05405, USA
| | - Emily E Torsney
- Department of Neurological Sciences and Neuroscience Graduate Program, University of Vermont, Burlington, VT 05401, USA
| | - Roxana Del Rio-Guerra
- Harry Hood Bassett Flow Cytometry and Cell Sorting Facility, University of Vermont, Burlington, VT 05401, USA
| | - Matthew E Poynter
- Department of Medicine, Pulmonary Disease and Critical Care, University of Vermont, Burlington, VT 05405, USA
| | - Jeffrey L Spees
- Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, VT 05446, USA; Department of Neurological Sciences and Neuroscience Graduate Program, University of Vermont, Burlington, VT 05401, USA.
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14
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Smeijer JD, Kohan DE, Dhaun N, Noronha IL, Liew A, Heerspink HJL. Endothelin receptor antagonists in chronic kidney disease. Nat Rev Nephrol 2025; 21:175-188. [PMID: 39643698 DOI: 10.1038/s41581-024-00908-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2024] [Indexed: 12/09/2024]
Abstract
Endothelin-1 is a potent vasoconstrictor that has diverse physiological functions in the kidney, including in the regulation of blood flow and glomerular filtration, electrolyte homeostasis and endothelial function. Overexpression of endothelin-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) that target the endothelin A (ETA) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ETA ERA, atrasentan, reduced albuminuria and kidney function decline. Concerns about the increased risks of fluid retention and heart failure with ERA use have led to the design of further trials to optimize dosing and patient selection. More recent studies have shown that the dual ETA receptor and angiotensin receptor blocker, sparsentan, preserved kidney function with minimal fluid retention in patients with IgA nephropathy. Moreover, combined administration of a low dose of the ETA-selective ERA, zibotentan, with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This Review describes our current understanding of the use of ERAs in patients with CKD to guide their optimal safe and effective use in clinical practice.
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Affiliation(s)
- J David Smeijer
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Donald E Kohan
- Division of Nephrology, University of Utah Health, Salt Lake City, UT, USA
| | - Neeraj Dhaun
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Irene L Noronha
- Division of Nephrology, University of Sao Paulo Medical School, Sao Paulo, Brazil
- George Institute for Global Health, Sydney, New South Wales, Australia
| | - Adrian Liew
- George Institute for Global Health, Sydney, New South Wales, Australia
- Mount Elizabeth Novena Hospital, Singapore, Singapore
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
- George Institute for Global Health, Sydney, New South Wales, Australia.
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15
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Airo M, Frishman WIH, Aronow WS. New Therapy Update Aprocitentan: An Endothelin Receptor Antagonist for the Treatment of Drug-Resistant Systemic Hypertension. Cardiol Rev 2025; 33:114-119. [PMID: 37530539 DOI: 10.1097/crd.0000000000000591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/03/2023]
Abstract
Resistant hypertension (RH) is the state of uncontrolled blood pressure in the face of ostensibly optimal pharmacological intervention. It accounts for roughly one in six cases of hypertension, and is associated with more severe morbidity and mortality outcomes than is non-RH. The prevalence of RH implies a currently unmanaged pathology, which may involve the potent vasoconstrictor endothelin. Several endothelin receptor antagonists are currently marketed for pulmonary arterial hypertension, but none so far has been marketed for RH. Aprocitentan is currently in development, an endothelin receptor antagonist that effectively produces clinically significant and sustained decreases in systolic and diastolic blood pressure in the setting of RH.
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Affiliation(s)
- Michael Airo
- From the Medicine, New York Medical College, Valhalla, NY
| | - WIlliam H Frishman
- Department of Cardiology and Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - Wilbert S Aronow
- Department of Cardiology and Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY
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16
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Zhang Y, Tian X, Chen L, Zhao S, Tang X, Liu X, Zhou D, Tang C, Geng B, Du J, Jin H, Huang Y. Endogenous hydrogen sulfide persulfidates endothelin type A receptor to inhibit pulmonary arterial smooth muscle cell proliferation. Redox Biol 2025; 80:103493. [PMID: 39823888 PMCID: PMC11787542 DOI: 10.1016/j.redox.2025.103493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/27/2024] [Accepted: 01/07/2025] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND The binding of endothelin-1 (ET-1) to endothelin type A receptor (ETAR) performs a critical action in pulmonary arterial smooth muscle cell (PASMC) proliferation leading to pulmonary vascular structural remodeling. More evidence showed that cystathionine γ-lyase (CSE)-catalyzed endogenous hydrogen sulfide (H2S) was involved in the pathogenesis of cardiovascular diseases. In this study, we aimed to explore the effect of endogenous H2S/CSE pathway on the ET-1/ETAR binding and its underlying mechanisms in the cellular and animal models of PASMC proliferation. METHODS AND RESULTS Both live cell imaging and ligand-receptor assays revealed that H2S donor, NaHS, inhibited the binding of ET-1/ETAR in human PASMCs (HPASMCs) and HEK-293A cells, along with an inhibition of ET-1-activated HPASMC proliferation. While, an upregulated Ki-67 expression by the pulmonary arteries, a marked pulmonary artery structural remodeling, and an increased pulmonary artery pressure were observed in CSE knockout (CSE-KO) mice with a deficient H2S/CSE pathway compared with those in the wild type (WT) mice. Meanwhile, NaHS rescued the enhanced binding of ET-1 with ETAR and cell proliferation in the CSE-knockdowned HPASMCs. Moreover, the ETAR antagonist BQ123 blocked the enhanced proliferation of CSE-knockdowned HPASMCs. Mechanistically, ETAR persulfidation was reduced in the lung tissues of CSE-KO mice compared to that in WT mice, which could be reversed by NaHS treatment. Similarly, NaHS persulfidated ETAR in HPASMCs and HEK-293A cells. Whereas a thiol reductant dithiothreitol (DTT) reversed the H2S-induced ETAR persulfidation and further blocked the H2S-inhibited binding of ET-1/ETAR and HPASMC proliferation. Furthermore, the mutation of ETAR at cysteine (Cys) 69 abolished the persulfidation of ETAR by H2S, and subsequently blocked the H2S-suppressed ET-1/ETAR binding and HPASMC proliferation. CONCLUSION Endogenous H2S persulfidated ETAR at Cys69 to inhibit the binding of ET-1 to ETAR, subsequently suppressed PASMC proliferation, and antagonized pulmonary vascular structural remodeling.
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MESH Headings
- Humans
- Cell Proliferation/drug effects
- Animals
- Hydrogen Sulfide/metabolism
- Hydrogen Sulfide/pharmacology
- Pulmonary Artery/metabolism
- Pulmonary Artery/cytology
- Mice
- Receptor, Endothelin A/metabolism
- Receptor, Endothelin A/genetics
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/cytology
- Cystathionine gamma-Lyase/metabolism
- Cystathionine gamma-Lyase/genetics
- HEK293 Cells
- Mice, Knockout
- Endothelin-1/metabolism
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/cytology
- Sulfides/pharmacology
- Sulfides/metabolism
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Affiliation(s)
- Yanan Zhang
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, PR China
| | - Xiaoyu Tian
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, PR China
| | - Liangyi Chen
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing, 100871, PR China; National Center for Nanoscience and Technology, Beijing, 100871, PR China
| | - Shiqun Zhao
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing, 100871, PR China; National Center for Nanoscience and Technology, Beijing, 100871, PR China
| | - Xinjing Tang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, No. 38, Xueyuan Rd, Beijing, 100191, PR China
| | - Xin Liu
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, PR China
| | - Dan Zhou
- Department of Cardiology, Wuhan Children's Hospital, Wuhan, PR China
| | - Chaoshu Tang
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191, PR China; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, PR China
| | - Bin Geng
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
| | - Junbao Du
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, PR China; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, PR China
| | - Hongfang Jin
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, PR China.
| | - Yaqian Huang
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, PR China.
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17
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Mangoni AA, Zinellu A. Endothelin-1 as a Candidate Biomarker of Systemic Sclerosis: A GRADE-Assessed Systematic Review and Meta-Analysis With Meta-Regression. Biomark Insights 2025; 20:11772719251318555. [PMID: 39990053 PMCID: PMC11846126 DOI: 10.1177/11772719251318555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 01/20/2025] [Indexed: 02/25/2025] Open
Abstract
Background There is an ongoing search for novel biomarkers of vascular dysfunction, extent of fibrosis and organ involvement in systemic sclerosis (SSc). Objectives We critically appraised the studies investigating the circulating concentrations of endothelin-1 in SSc patients and healthy controls. Design This was a systematic review with meta-analysis. Data sources and methods We searched electronic databases (PubMed, Scopus, and Web of Science) from inception to 15 June 2024. We assessed the risk of bias and the certainty of evidence using the JBI Critical Appraisal Checklist and GRADE, respectively. Results Endothelin-1 concentrations were significantly higher in SSc patients than in controls (26 studies; standardised mean difference, SMD = 0.98, 95% CI 0.73-1.23, P < .001; moderate certainty of evidence). In SSc patients, there were no significant differences in endothelin-1 concentrations between those with limited and diffuse cutaneous SSc (10 studies; SMD = 0.32, 95% CI -0.07 to 0.71 P = .11; very low certainty), and with and without digital ulcers (5 studies; SMD = 0.82, 95% CI -0.06 to 1.69, P = .066; very low certainty), pulmonary arterial hypertension (7 studies; SMD = 0.22, 95% CI -0.01 to 0.45, P = .066; very low certainty) or interstitial lung disease (3 studies; SMD = 0.09, 95% CI -0.18 to 0.35, P = .51; very low certainty). There was limited evidence in SSc patients with different video capillaroscopy pattern and telangiectasias. Subgroup and meta-regression analyses showed significant associations between the effect size and geographical location (studies investigating SSc patients and controls), year of publication (studies investigating SSc patients with limited and diffuse cutaneous SSc), and biological matrix assessed (studies investigating SSc patients with and without digital ulcers). Conclusion The results of this systematic review and meta-analysis highlight the potential role of endothelin-1 as a candidate biomarker of SSc. Further research is warranted to determine the utility of measuring endothelin-1 in SSc subgroups with different extent of fibrosis and organ involvement. Registration PROSPERO registration number - CRD42024566461.
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Affiliation(s)
- Arduino A Mangoni
- Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, SA, Australia
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
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18
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Masi I, Ottavi F, Caprara V, Rio DD, Kunkl M, Spadaro F, Licursi V, Tuosto L, Bagnato A, Rosano' L. The extracellular matrix protein type I collagen and fibronectin are regulated by β-arrestin-1/endothelin axis in human ovarian fibroblasts. J Exp Clin Cancer Res 2025; 44:64. [PMID: 39985042 PMCID: PMC11844176 DOI: 10.1186/s13046-025-03327-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/12/2025] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND The invasive and metastatic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and stroma, which include extracellular matrix (ECM) and cellular components, including cancer-associated fibroblasts (CAFs). Soluble factors secreted by cancer and stromal cells contribute to stroma remodeling through the secretion of ECM proteins, providing a favorable environment for cancer cell dissemination. The peptide endothelin-1 (ET-1), through two G protein-coupled receptors (GPCR), endothelin receptor type A (ETAR) and B (ETBR), acts on both cancer and stromal cells, engaging the protein β-arrestin1 (β-arr1), to bolster SOC progression. However, its role in the regulation of the ECM proteins by ovarian fibroblasts is not understood. This study delves into the role of ET-1 as a regulator of type I collagen (Col1) and fibronectin (FN). METHODS We used human primary ovarian fibroblasts (HOFs) and CAFs. The expression of Col1 (COL1A1) and FN (FN1) were detected by western blotting (WB), quantitative real time-polymerase chain reaction (qRT-PCR), immunofluorescence (IF), and confocal laser scanning microscopy (CLSM) in cells and tumor tissue sections from mice xenografts, while the transcription of COL1A1 was detected by luciferase reporter gene assay. The nuclear function of β-arr1 was evaluated by silencing and rescue expression with wild-type (WT) and nuclear mutant plasmid constructs, RNA seq and differential gene expression and gene sets enrichment analyses. The prognostic role of COL1A1, FN1, EDN1 (ET-1) and ARRB1 (β-arr1) gene expression was evaluated using the Kaplan-Meier plotter database and clinical ovarian cancer tissue samples. RESULTS We demonstrated that ET-1 boosts Col1 and FN expression in HOFs, akin to ovarian CAF levels. Both receptors are implicated, evident from inhibitory effects after ETAR or ETBR antagonist treatments and notably with bosentan, a dual antagonist, in vitro and in vivo. At the molecular level, ET-1 triggers the activation of COL1A1 promoter activity and its enhanced expression via β-arr1 nuclear function. Transcriptome analysis of β-arr1-silenced HOFs confirms the nuclear role of β-arr1 in collagen and ECM remodeling-related protein transcriptional regulation. Accordingly, a high level of EDN1/ARRB1 expression in combination with either COL1A1 or FN1 is associated with the poor prognosis of SOC patients. CONCLUSIONS These findings hint at ET-1 involvement in ECM remodeling and early SOC stages by modulating the expression of Col1 and FN. Targeting ET-1 signaling with ETAR/ETBR antagonists might interfere with the ability of CAFs to produce key ECM proteins in this tumor.
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Affiliation(s)
- Ilenia Masi
- Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, Italy
| | - Flavia Ottavi
- Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, Italy
| | - Valentina Caprara
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Danila Del Rio
- Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, Italy
| | - Martina Kunkl
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University, Rome, Italy
- Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, Italy
| | - Francesca Spadaro
- Confocal Microscopy Unit, Core Facilities, Istituto Superiore di Sanità, Rome, Italy
| | - Valerio Licursi
- Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, Italy
| | - Loretta Tuosto
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University, Rome, Italy
| | - Anna Bagnato
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Laura Rosano'
- Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, Italy.
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19
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Atanasova DY, Rashev PI, Mourdjeva MS, Pupaki DV, Hristova A, Dandov AD, Lazarov NE. Altered Expression Levels of Angiogenic Peptides in the Carotid Body of Spontaneously Hypertensive Rats. Int J Mol Sci 2025; 26:1620. [PMID: 40004084 PMCID: PMC11855809 DOI: 10.3390/ijms26041620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/09/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
The carotid body (CB), the main peripheral arterial chemoreceptor, exhibits considerable structural and neurochemical plasticity in response to pathological conditions such as high blood pressure. Previous studies have shown that morphological alterations in the hypertensive CB are characterized by enlarged parenchyma due to cellular hypertrophy and hyperplasia, and vasodilation. To test whether hypertension can also induce neoangiogenesis and modulate its chemosensory function, we examined the immunohistochemical expression of two angiogenic factors, vascular endothelial growth factor (VEGF) and endothelin-1 (ET), and their corresponding receptors in the CB of adult spontaneously hypertensive rats (SHRs), and compared their expression patterns to that of age-matched normotensive Wistar rats (NWR). We found an increased VEGF-A and B, and VEGFR-2 expression in glomus and endothelial cells in the enlarged CB glomeruli of SHRs compared with that in NWR. Conversely, weaker immunoreactivity to VEGFR-1 was detected in cell clusters of the hypertensive CB. The expression of endothelin-converting enzyme 1 and its receptor ETA was higher in a subset of glomus cells in the normotensive CB, while the immunoreactivity to the ETB receptor was enhanced in endothelial cells of CB blood vessels in SHRs. The elevated endothelial expression of VEGF and ET-1 suggests their role as local vascular remodeling factors in the adaptation to hypertension, though their involvement in the cellular rearrangement and modulation of chemosensory function could also be implied.
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Affiliation(s)
- Dimitrinka Y. Atanasova
- Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria;
- Department of Anatomy, Faculty of Medicine, Trakia University, 6003 Stara Zagora, Bulgaria
| | - Pavel I. Rashev
- Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria;
- Institute of Biology and Immunology of Reproduction “Acad. Kiril Bratanov”, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (M.S.M.); (D.V.P.)
| | - Milena S. Mourdjeva
- Institute of Biology and Immunology of Reproduction “Acad. Kiril Bratanov”, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (M.S.M.); (D.V.P.)
| | - Despina V. Pupaki
- Institute of Biology and Immunology of Reproduction “Acad. Kiril Bratanov”, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (M.S.M.); (D.V.P.)
| | - Anita Hristova
- Faculty of Medicine, Trakia University, 6003 Stara Zagora, Bulgaria;
| | - Angel D. Dandov
- Department of Anatomy and Histology, Medical University of Sofia, 1431 Sofia, Bulgaria;
| | - Nikolai E. Lazarov
- Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria;
- Department of Anatomy and Histology, Medical University of Sofia, 1431 Sofia, Bulgaria;
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20
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Heerspink HJL, Jardine M, Kohan DE, Lafayette RA, Levin A, Liew A, Zhang H, Lodha A, Gray T, Wang Y, Renfurm R, Barratt J. Atrasentan in Patients with IgA Nephropathy. N Engl J Med 2025; 392:544-554. [PMID: 39460694 DOI: 10.1056/nejmoa2409415] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2024]
Abstract
BACKGROUND Patients with IgA nephropathy and severe proteinuria have a high lifetime risk of kidney failure. The efficacy and safety of the selective endothelin type A receptor antagonist atrasentan in reducing proteinuria in patients with IgA nephropathy are incompletely understood. METHODS We are conducting a phase 3, multinational, double-blind, randomized, controlled trial involving adults with biopsy-proven IgA nephropathy, a total urinary protein excretion of at least 1 g per day, and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. Patients were randomly assigned to receive atrasentan (0.75 mg per day) or matched placebo for 132 weeks. The primary outcome, assessed at a prespecified interim analysis of data from the first 270 patients in the main stratum, was the change in the 24-hour urinary protein-to-creatinine ratio from baseline to week 36; the change was estimated with the use of a repeated-measures model. (An exploratory stratum of patients who were receiving a sodium-glucose cotransporter 2 inhibitor were included in a separate analysis.) Safety analyses were based on adverse events across the entire main stratum. RESULTS A total of 340 patients were recruited into the main stratum. Among the first 270 patients in the main stratum (135 per trial group) who completed the week 36 visit, the geometric mean percentage change in the urinary protein-to-creatinine ratio relative to baseline was significantly greater with atrasentan (-38.1%) than with placebo (-3.1%), with a geometric mean between-group difference of -36.1 percentage points (95% confidence interval, -44.6 to -26.4; P<0.001). The percentage of patients with adverse events did not differ substantially between the two groups. Fluid retention was reported by 19 of 169 patients (11.2%) in the atrasentan group and in 14 of 170 (8.2%) in the placebo group but did not lead to discontinuation of the trial regimen. No apparent cases of cardiac failure or severe edema occurred. CONCLUSIONS In this prespecified interim analysis, atrasentan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo in patients with IgA nephropathy. (Funded by Novartis; ALIGN ClinicalTrials.gov number, NCT04573478.).
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Affiliation(s)
- Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Meg Jardine
- National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney
| | - Donald E Kohan
- Division of Nephrology, University of Utah Health, Salt Lake City
| | | | - Adeera Levin
- University of British Columbia, Vancouver, Canada
| | | | - Hong Zhang
- Peking University First Hospital, Beijing
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21
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Moedt E, Wasehuus VS, Heerspink HJL. Selective endothelin A receptor antagonism in chronic kidney disease: improving clinical application. Nephrol Dial Transplant 2025; 40:i37-i46. [PMID: 39907539 DOI: 10.1093/ndt/gfae214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Indexed: 02/06/2025] Open
Abstract
Endothelin-1 (ET-1) is a peptide that is involved in various chronic diseases including cardiovascular and kidney disease. ET-1 can bind to two receptors, endothelin A (ETA) and endothelin B (ETB), which are found in different organs and tissues. When ET-1 binds to the ETA receptor, it causes blood vessels to narrow, while binding of ET-1 to the ETB receptor causes blood vessels to widen. These receptors help regulate fluid and electrolyte balance in the kidneys, as well as the kidney's ability to filter various substances out of the body. Overactivation of ET-1 can occur in people with diabetes or obesity, which can damage the structure and function of the kidney.Studies in mice and humans with kidney disease have shown that blocking the ETA receptor improves kidney health. As a result, medicines that specifically block the ETA receptor, known as endothelin receptor antagonists (ERAs), are a promising option for treating these kidney diseases. The first ERA (sparsentan) is now available for use in patients with immunoglobulin A (IgA) nephropathy, a specific type of kidney disease. It should be noted that ERAs can cause side effects. Fluid retention, which can increase the risk of heart failure, is a side effect that is particularly observed in patients with type 2 diabetes and severe kidney disease. This side effect is less often observed in patients with IgA nephropathy or patients without diabetes.Treatment strategies to optimize safe and effective use of ETA blockers are being developed. Overall, these insights offer hope for better care of patients with kidney disease. ABSTRACT Endothelin-1 (ET-1) is a 21-amino acid peptide involved in numerous cardiovascular and renal processes. ET-1 can bind to endothelin receptor A (ETA) and endothelin receptor B (ETB), which are found in various organs and tissues. In general, binding of ET-1 to the ETA receptor causes vasoconstriction, whereas activation of the ETB receptor leads to vasodilation. In the kidney, endothelin receptors regulate fluid and electrolyte balance, regional blood flow and glomerular filtration rate. In pathological conditions, ET-1 promotes kidney injury through adverse effects on the endothelial glycocalyx, podocytes and mesangial cells, and stimulating inflammation and fibrosis in the tubules. In experimental and clinical studies, inhibition of the ETA receptor has been shown beneficial in a variety of kidney diseases. These include diabetic kidney disease, immunoglobulin A nephropathy, focal segmental glomerulosclerosis and Alport syndrome. Accordingly, selective ETA endothelin receptor antagonists (ERA) may prove a viable therapeutic option in these diseases. However, clinical application is challenged by the occurrence of fluid retention which can lead to heart failure, in particular in patients with severe CKD. Concomitant use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) may mitigate these adverse effects through their diuretic actions. The development of highly selective ETA antagonists, such as atrasentan and zibotentan, and the opportunities of combining these with SGLT2i, holds promise to optimize efficacy and safety of ERAs in clinical practice.
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Affiliation(s)
- Erik Moedt
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- The George Institute for Global Health, Sydney, Australia
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22
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Koch A, Reinhardt P, Elicin O, Aebersold DM, Schanne DH. Predictive biomarkers of radiotherapy- related dermatitis, xerostomia, mucositis and dysphagia in head and neck cancer: A systematic review. Radiother Oncol 2025; 203:110689. [PMID: 39706342 DOI: 10.1016/j.radonc.2024.110689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 12/10/2024] [Accepted: 12/13/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND Radiotherapy is essential for treating head and neck cancer but often leads to severe toxicity. Traditional predictors include anatomical location, tumor extent, and dosimetric data. Recently, biomarkers have been explored to better predict and understand toxicity. This review aims to summarize the current literature, assess data quality, and guide future research. METHODS Two reviewers independently screened EMBASE and PubMed for studies published between 2010 and 2023. Endpoints were dermatitis, mucositis, sticky saliva/xerostomia, and dysphagia. Statistical analysis was performed using R, and bias assessed via a modified QUIPS questionnaire. Pathway analysis was conducted using gProfiler. The study adhered to PRISMA and COSMOS-E guidelines and was registered in the PROSPERO database (#CRD42023361245). RESULTS Of 2,550 abstracts, 69 publications met the inclusion criteria. These studies involved a median of 81 patients, primarily male (75 %), with common primary tumors in the nasopharynx (32 %) and oropharynx (27 %). Most patients (84 %) had advanced disease (stage III/IV). The most frequently studied biomarkers were DNA-based single-nucleotide polymorphisms (SNPs, 59 %), salivary proteins (13 %), and bacteria (10 %). Ten statistically-significant biomarkers (all SNPs) in low-bias publications were identified, particularly in DNA repair and cell detoxification pathways. Data quality was often poor and few validation studies were present in the dataset. CONCLUSION This review provides an overview of the research landscape, highlights research gaps and provides recommendations for future research directions. We identified several potential biomarkers, particularly in DNA repair pathways, that align with current understanding of radiation-induced cell damage. However, the overall data quality was poor, with key clinical variables often missing. Overall, rigorous standardization of reporting, validation studies and multi-center collaborations to increase study power and sample sizes are necessary to build high-level evidence for clinical application.
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Affiliation(s)
- Alexander Koch
- Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Philipp Reinhardt
- Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Olgun Elicin
- Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Daniel M Aebersold
- Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Daniel H Schanne
- Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland; Graduate School for Health Sciences, University of Bern, Switzerland.
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23
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Okumura E, Nakaya K, Otsuka K, Jimbo H. Treatment Outcomes of Clazosentan Use During the Perioperative Period for Subarachnoid Hemorrhage. Cureus 2025; 17:e79497. [PMID: 40135022 PMCID: PMC11934823 DOI: 10.7759/cureus.79497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2025] [Indexed: 03/27/2025] Open
Abstract
Background Fasudil hydrochloride hydrate has been traditionally administered in the perioperative management of aneurysmal subarachnoid hemorrhage (aSAH) in Japan for the prevention of delayed cerebral ischemia (DCI) secondary to cerebral vasospasm. While clazosentan, a selective endothelin receptor antagonist, was introduced in April 2022 as an alternative therapeutic option for the same indication, comparative data regarding the therapeutic effectiveness between these agents remains limited. Therefore, this study investigated the differences in treatment outcomes between traditional fasudil hydrochloride hydrate and clazosentan in the perioperative management of aSAH. Materials and methods We retrospectively analyzed aSAH cases treated at our hospital from April 2020 to April 2024. Cases were stratified into either the conventional (fasudil hydrochloride hydrate) or clazosentan group. The primary endpoint was the frequency of DCI associated with cerebral vasospasm. The secondary endpoints were moderate or severe cerebral vasospasm within 14 days of aSAH onset, frequency of rescue therapy, modified Rankin scale (mRS) ≤3 at discharge and hospital stay duration. The postoperative incidence of symptomatic pulmonary edema and mortality assessed safety. Results The study analyzed 104 cases, 61 in the conventional group and 43 in the clazosentan group. The frequency of DCI did not differ between the conventional and clazosentan groups (three cases vs. one case, respectively). Similarly, no significant differences were observed in moderate or severe cerebral vasospasm, rescue therapy, or hospital stay duration. The conventional group had 29 cases with mRS ≤3 at discharge compared with 31 in the clazosentan group. A significantly higher incidence of symptomatic pulmonary edema was observed in the clazosentan group, with 15 cases vs. eight cases in the conventional group. No difference was observed in mortality at discharge. Conclusions We compared treatment outcomes between fasudil hydrochloride hydrate and clazosentan for aSAH. While clazosentan showed a non-significant trend toward lower DCI frequency, it was associated with increased symptomatic pulmonary edema. Given the study's limitations, larger-scale research with matched baseline characteristics is needed to definitively evaluate these agents' comparative efficacy.
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Affiliation(s)
- Eitaro Okumura
- Department of Neurosurgery, Tokyo Medical University Hachioji Medical Center, Hachioji, JPN
| | - Kohei Nakaya
- Department of Neurosurgery, Tokyo Medical University Hachioji Medical Center, Hachioji, JPN
| | - Kunitoshi Otsuka
- Department of Neurosurgery, Tokyo Medical University Hachioji Medical Center, Hachioji, JPN
| | - Hiroyuki Jimbo
- Department of Neurosurgery, Tokyo Medical University Hachioji Medical Center, Hachioji, JPN
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Ba L, Zhao Z, Zhang C, Chu Y, Wu C. Expression and prognostic impact of hypoxia- and immune escape-related genes in triple-negative breast cancer: A comprehensive analysis. Int Immunopharmacol 2025; 146:113810. [PMID: 39689602 DOI: 10.1016/j.intimp.2024.113810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/23/2024] [Accepted: 12/04/2024] [Indexed: 12/19/2024]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks effective therapeutic options. Hypoxia and immune escape are critical factors that contribute to the progression of and resistance to therapy in patients with TNBC. Nevertheless, few studies have comprehensively analyzed hypoxia and immune escape in patients with TNBC. This study aimed to examine the expression of hypoxia- and immune escape-related genes in TNBC and their influence on prognosis. TNBC datasets were downloaded and processed from The Cancer Genome Atlas and Gene Expression Omnibus. Differential expression analysis identified 4949 differentially expressed genes, between TNBC and normal tissues. The intersection yielded 116 hypoxia- and immune escape-related differentially expressed genes (H&IERDEGs), including KIF4A, BIRC5, and BUB1. Enrichment analyses indicated that H&IERDEGs were significantly enriched in biological processes, including cell chemotaxis, leukocyte migration, and cytokine-cytokine receptor interaction. Subsequently, weighted gene co-expression network analysis identified 43 module genes that were found to define two TNBC subtypes. We constructed a prognostic risk model consisting of eight signature genes, which demonstrated a high predictive performance to predict the overall survival (OS) of patients with TNBC with an area under the curve (AUC) exceeding 0.9 at 1 year survival. This indicates that the model effectively differentiates between outcomes, reflecting its robust performance. This study investigated the roles and potential mechanisms of hypoxia- and immune escape-related genes in TNBC and constructed a prognostic risk model with a high predictive performance. These findings offer novel molecular markers and potential therapeutic targets for TNBC.
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Affiliation(s)
- Li Ba
- Department of Ultrasound, First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China
| | - Zhiyu Zhao
- Department of Ultrasound, First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Laboratory of Medical Genetics, Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin 150001, PR China
| | - Chunmei Zhang
- Department of Ultrasound, First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China
| | - Yinzhu Chu
- Department of Ultrasound, First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China
| | - Changjun Wu
- Department of Ultrasound, First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
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Haferanke J, Baumgartner L, Willinger L, Oberhoffer-Fritz R, Schulz T. Molecular Mechanisms of Vascular Tone in Exercising Pediatric Populations: A Comprehensive Overview on Endothelial, Antioxidative, Metabolic and Lipoprotein Signaling Molecules. Int J Mol Sci 2025; 26:1027. [PMID: 39940797 PMCID: PMC11817131 DOI: 10.3390/ijms26031027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/20/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Vasoactive molecules are central regulators of vascular tone, angiogenesis and inflammation. Key molecular agents include nitric oxide (NO), endothelin-1 (ET-1), prostacyclin, free triiodothyronine (fT3), leptin, low-density lipoprotein (LDL), high-density lipoprotein (HDL), superoxide dismutase (SOD), and glutathione peroxidase (GPX). Dysregulation of these compounds can lead to endothelial dysfunction, an early predictor of atherosclerosis and cardiovascular diseases (CVD). Maintaining endothelial health is thus essential for vascular homeostasis and cardiovascular risk prevention. Regular exercise serves as a vital protective measure against CVD and the risk of cardiovascular conditions. However, young athletes often significantly exceed recommended levels of training load, engaging in highly intensive training that leads to substantial physiological adaptations. Despite this, research on the impact of exercise on vasoactive substances in children and adolescents, particularly young athletes, is limited and inconsistent. Most studies focus on those with pre-existing conditions, like obesity or diabetes mellitus. Existing findings suggest exercise may favorably affect vascular biomarkers in youth, but methodological variations hinder consistent conclusions. This literature review examines 68 studies on the effects of exercise on vascular molecules in children and adolescents, young athletes, and children and adolescents with pre-existing conditions, offering deeper insights into how exercise may influence vascular health at the molecular level.
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Affiliation(s)
- Jonas Haferanke
- Department Health and Sport Sciences, Institute of Preventive Pediatrics, TUM School of Medicine and Health, Technical University of Munich (TUM), 80992 Munich, Germany
| | | | | | | | - Thorsten Schulz
- Department Health and Sport Sciences, Institute of Preventive Pediatrics, TUM School of Medicine and Health, Technical University of Munich (TUM), 80992 Munich, Germany
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Herbet A, Hautière M, Jean-Alphonse F, Vivier D, Leboeuf C, Costa N, Mabondzo A, Bousquet G, Denat F, Reiter E, Boquet D. Targeting the activated allosteric conformation of the endothelin receptor B in melanoma with an antibody-drug conjugate: mechanisms and therapeutic efficacy. BJC REPORTS 2025; 3:3. [PMID: 39833448 PMCID: PMC11747117 DOI: 10.1038/s44276-024-00109-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/02/2024] [Accepted: 10/13/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Endothelin 1 receptors are one of the drivers of tumor progression in many cancers. Inhibition of their signaling pathways with antagonist drugs has been the subject of numerous clinical trials, but the results have not met expectations probably due to the high endothelin concentrations in the tumor microenvironment and their unusually high affinity for their receptors. METHODS We previously reported the rendomab B49 antibody (RB49) exhibiting a preferential affinity for the activated conformation of human endothelin B receptor (ETB), not displaced by high endothelin levels, and without any pharmacological properties that could inhibit the division of melanoma cells. In this context, we have developed xiRB49-MMAE, a chimeric antibody-drug conjugated (ADC) to monomethyl auristatin E. We have characterized its physicochemical properties, studied its binding mechanisms, and evaluated its therapeutic potential in a preclinical model. Immunohistochemical analysis of metastatic melanoma lymph nodes evaluated RB49 as a diagnostic tool for patient stratification. RESULTS xiRB49-MMAE showed high efficacy against melanoma cells and ETB+ xenograft tumor models. IHC studies indicated that 100% of melanoma patient lymph node biopsies were RB49-positive. CONCLUSIONS xiRB49-MMAE is a promising drug candidate for clinical trials in ETB+ tumors. RB49 could be used as a diagnostic tool for patient stratification.
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Affiliation(s)
- Amaury Herbet
- Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France
| | - Marie Hautière
- Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France
| | - Frédéric Jean-Alphonse
- INRAE, CNRS, Université de Tours, PRC, Nouzilly, France
- Inria, Inria Saclay-Ile-de-France, Palaiseau, France
| | - Delphine Vivier
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB UMR CNRS 6302, Université de Bourgogne, Dijon, France
| | | | - Narciso Costa
- Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France
| | - Aloïse Mabondzo
- Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France
| | - Guilhem Bousquet
- Université Paris Cité, INSERM, UMR_S942 MASCOT, Paris, France
- Université Sorbonne Paris Nord, Villetaneuse, France
| | - Franck Denat
- Inria, Inria Saclay-Ile-de-France, Palaiseau, France
| | - Eric Reiter
- INRAE, CNRS, Université de Tours, PRC, Nouzilly, France
- Inria, Inria Saclay-Ile-de-France, Palaiseau, France
| | - Didier Boquet
- Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France.
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Huang Z, Yu P, Hu J, Zhang W. Comparative Pharmacokinetics and Bioequivalence of 2 Formulations of Bosentan Dispersible Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions. Clin Pharmacol Drug Dev 2025. [PMID: 39828968 DOI: 10.1002/cpdd.1516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 01/08/2025] [Indexed: 01/22/2025]
Abstract
Bosentan is a dual endothelin receptor antagonist widely used in the treatment of pulmonary artery hypertension. However, there are few reports on the pharmacokinetics (PK) and bioequivalence of bosentan dispersible tablets (32 mg) in the Chinese population. This study aimed to evaluate the PK characteristics and bioequivalence of the test and reference formulations of bosentan dispersible tablets in healthy Chinese volunteers under fasting and fed conditions. A randomized, single-dose, 2-sequence, 2-period crossover study (fasting) and a 4-period replicate crossover study (fed) were conducted with 48 and 30 healthy volunteers, respectively. The bosentan plasma concentrations were measured by a validated ultra-performance liquid chromatography coupled with a tandem mass spectrometry method, and PK parameters were analyzed using noncompartmental methods. The bioequivalence statistical analysis showed that 90% confidence intervals for the geometric mean ratios of peak plasma concentration, area under the concentration-time curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity for the test and reference formulations were within the bioequivalence range of 80%-125% under both fasting and fed conditions. After the administration of bosentan dispersible tablets under fed conditions, the systemic exposure (based on AUC from time zero to infinity) was increased by approximately 15%-20%. These findings confirm the bioequivalence of the 2 formulations, and both formulations were well tolerated, with no safety-related adverse events reported. Given the wide therapeutic dose range of bosentan dispersible tablets for the treatment of pulmonary artery hypertension in children, the impact of food on its PK is not considered clinically significant.
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Affiliation(s)
- Zhaoming Huang
- Department of Medical Cosmetology, Xianning Central Hospital, The First Affiliated Hosptial of Hubei University of Science and Technology, Xianning, Hubei, P.R. China
| | - Panpan Yu
- Department of Medical Cosmetology, Xianning Central Hospital, The First Affiliated Hosptial of Hubei University of Science and Technology, Xianning, Hubei, P.R. China
| | - Jiawei Hu
- Office of Drug Clinical Trial Institution, Xianning Central Hospital, The First Affiliated Hosptial of Hubei University of Science And Technology, Xianning, Hubei, P.R. China
| | - Wanyong Zhang
- Department of Pathology, Xianning Central Hospital, The First Affiliated Hosptial of Hubei University of Science and Technology, Xianning, Hubei, P.R. China
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Mutchler AL, Zhong J, Yang HC, Zhao S, Crescenzi R, Taylor S, Rao RL, Shelton EL, Kirabo A, Kon V. ET-3/ETBR Mediates Na +-Activated Immune Signaling and Kidney Lymphatic Dynamics. Circ Res 2025; 136:194-208. [PMID: 39676651 PMCID: PMC11800760 DOI: 10.1161/circresaha.124.324890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 11/14/2024] [Accepted: 12/02/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Lymphatic collecting vessels in the kidney are critical in clearing interstitial fluid, macromolecules, and infiltrating immune cells. Dysfunction of the lymphatic vessels can disrupt this process and exacerbate injury-associated inflammation in many disease conditions. We previously found that sodium accumulates within the kidney interstitium during proteinuric kidney injury and elevated sodium environments stimulate isolevuglandin production in antigen-presenting cells, stimulating T cells, and modulating inflammatory responses. In the present study, we investigated whether proteinuric injury increases production of isolevuglandin-adduct formation in antigen-presenting cells, their effects on lymphatic endothelial cells (LECs), and the role of the ET-3 (endothelin-3)/ETBR (endothelin type B receptor) on lymphatic vessel function. METHODS We used a mouse model of nephrotoxin-induced proteinuric injury to show that proteinuric injury expanded the kidney lymphatic network and to immunophenotype the infiltrating immune cells. To determine mechanisms, we analyzed the interaction of migratory immune cells and LECs using an in vitro transwell migration assay, bulk RNA sequencing, and flow cytometric analysis. To determine the effect of ET-3/ETBR axis on lymphatic vessel contractility, we analyzed microdissected lymphangions utilizing a vessel perfusion chamber. RESULTS We found that animals with proteinuric injury have increased kidney lymphangiogenesis, isolevuglandin-producing dendritic cells, and IFN (interferon)-γ-producing CD4+T cells. The sodium avid environment present in kidney injury enhances the interaction between LECs and migratory antigen-presenting cells and LEC production of isolevuglandin-adducts. Elevated sodium environment-induced isolevuglandin-adduct formation facilitates the ET-3/ETBR communication between LECs and dendritic cells. In addition, the ET-3/ETBR axis modulates lymphatic collecting vessel pumping dynamics. CONCLUSIONS These findings reveal a novel mechanism linking the isolevuglandin-mediated ET-3/ETBR axis with LECs and infiltrating dendritic cells. ET-3/ETBR signaling in lymphatic vessel dynamics is a novel pathogenic component and a possible therapeutic target in kidney disease.
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Affiliation(s)
- Ashley L. Mutchler
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jianyong Zhong
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Hai-Chun Yang
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shilin Zhao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Rachelle Crescenzi
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shannon Taylor
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
| | - Roy L. Rao
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Elaine L. Shelton
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Annet Kirabo
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Valentina Kon
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Guo J, Xue S, Wang X, Wang L, Wen SY. Emerging insights on the role of Elovl6 in human diseases: Therapeutic challenges and opportunities. Life Sci 2025; 361:123308. [PMID: 39675554 DOI: 10.1016/j.lfs.2024.123308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/19/2024] [Accepted: 12/11/2024] [Indexed: 12/17/2024]
Abstract
ELOVL6, elongation-of-very-long-chain-fatty acids 6, a crucial enzyme in lipid metabolism, primarily responsible for the elongation of carbon chains of C12-C16 saturated fatty acids. It plays a significant role in various human diseases, particularly those associated with metabolic disorders related to fatty acid synthesis, such as insulin resistance, non-alcoholic fatty liver disease, cancer, and cardiovascular diseases. Emerging research also links ELOVL6 to kidney diseases, neurological conditions such as epilepsy, and pulmonary fibrosis. The enzyme's expression is regulated by various factors including diet, oxidative stress, and circadian rhythms. For instance, a high-carbohydrate diet can promote an increase in ELOVL6 expression. This abnormality leads to an accumulation of long-chain fatty acids and lipid deposition, ultimately resulting in pathological consequences across multiple systems in the body. As a biological target, ELOVL6 holds promise for diagnostic and therapeutic applications, with future research expected to uncover its mechanisms and therapeutic potential, paving the way for novel interventions in multiple disease areas. Here, the expression regulation and function of ELOVL6 in various human diseases are reviewed. This review underscores ELOVL6 as a significant therapeutic target for human diseases, with its potential for diagnostic and therapeutic applications anticipated to drive future research and enable innovative interventions in various pathological conditions.
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Affiliation(s)
- Jiao Guo
- College of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Shulan Xue
- College of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Xiaohui Wang
- College of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Li Wang
- College of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China.
| | - Shi-Yuan Wen
- College of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China.
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Wittczak A, Mazurek-Kula A, Banach M, Piotrowski G, Bielecka-Dabrowa A. Blood Biomarkers as a Non-Invasive Method for the Assessment of the State of the Fontan Circulation. J Clin Med 2025; 14:496. [PMID: 39860501 PMCID: PMC11765985 DOI: 10.3390/jcm14020496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/08/2025] [Accepted: 01/12/2025] [Indexed: 01/27/2025] Open
Abstract
The Fontan operation has become the primary palliative treatment for patients with a functionally univentricular heart. The population of patients with Fontan circulation is constantly growing and aging. As the number of Fontan patients surviving into adulthood increases, there is a clear need for research on how best to follow these patients and manage their complications. Monitoring blood biomarkers is a promising method for the non-invasive assessment of the Fontan circulation. In this article, we provide a comprehensive review of the available evidence on this topic. The following biomarkers were included: natriuretic peptides, red blood cell distribution width (RDW), cystatin C, high-sensitivity C-reactive protein, vitamin D, parathyroid hormone, von Willebrand factor, carbohydrate antigen 125, lipoproteins, hepatocyte growth factor, troponins, ST2 protein, galectin-3, adrenomedullin, endothelin-1, components of the renin-angiotensin-aldosterone system, norepinephrine, interleukin 6, tumor necrosis factor α, and uric acid. We did not find strong enough data to propose evidence-based recommendations. Nevertheless, significantly elevated levels of brain natriuretic peptide (BNP)/N-terminal prohormone of BNP (NT-proBNP) are most likely associated with the failure of the Fontan circulation. The use of the RDW is also promising. Several biomarkers appear to be useful in certain clinical presentations. Certainly, robust longitudinal, preferably multicenter, prospective studies are needed to determine the sensitivity, specificity, evidence-based cut-off values and overall predictive value of different biomarkers in monitoring Fontan physiology.
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Affiliation(s)
- Andrzej Wittczak
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz, 90-419 Lodz, Poland
- Department of Cardiology and Congenital Diseases of Adults, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland
| | - Anna Mazurek-Kula
- Department of Cardiology, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz, 90-419 Lodz, Poland
- Department of Cardiology and Congenital Diseases of Adults, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland
| | - Grzegorz Piotrowski
- Cardiooncology Department, Medical University of Lodz, 90-419 Lodz, Poland
- Cardiology Department, Nicolaus Copernicus Memorial Hospital, 93-513 Lodz, Poland
| | - Agata Bielecka-Dabrowa
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz, 90-419 Lodz, Poland
- Department of Cardiology and Congenital Diseases of Adults, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland
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He Q, Lin J, Mo C, Li G, Lu J, Sun Q, Cao L, Gan H, Sun Q, Yao J, Lian S, Wang W. Endothelin receptor antagonists (ERAs) can potentially be used as therapeutic drugs to reduce hypertension caused by small molecule tyrosine kinase inhibitors (TKIs). Front Pharmacol 2025; 15:1463520. [PMID: 39850566 PMCID: PMC11754196 DOI: 10.3389/fphar.2024.1463520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 12/23/2024] [Indexed: 01/25/2025] Open
Abstract
The emergence of targeted anti-tumor drugs has significantly prolonged the lifespan and improved the prognosis of cancer patients. Among these drugs, vascular endothelial growth factor (VEGF) inhibitors, particularly novel small molecule tyrosine kinase inhibitors (TKIs), are extensively employed as VEGF inhibitors; however, they are also associated with a higher incidence of complications, with hypertension being the most prevalent cardiovascular toxic side effect. Currently, it is widely accepted that TKIs-induced hypertension involves multiple mechanisms including dysregulation of the endothelin (ET) axis, reduced bioavailability of nitric oxide (NO), imbalance in NO-ROS equilibrium system, vascular rarefaction, and activation of epithelial sodium calcium channels; nevertheless, excessive activation of ET system appears to be predominantly responsible for this condition. Moreover, studies have demonstrated that ET plays a pivotal role in driving TKIs-induced hypertension. Therefore, this review aims to explore the significance of ET in the pathogenesis of hypertension induced by targeted anti-tumor drugs and investigate the potential therapeutic value of endothelin antagonists in managing hypertension caused by targeted anti-tumor drugs.
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Affiliation(s)
- Qingjian He
- Department of Breast and Thyroid Surgery, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Junling Lin
- Department of Cardiovascular Center, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Chanjuan Mo
- Department of Cardiovascular Center, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Guodong Li
- Department of Cardiovascular Center, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Jianzhong Lu
- Department of Cardiovascular Center, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Qiyin Sun
- Department of Cardiovascular Center, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Lijun Cao
- Department of Cardiovascular Center, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Haojian Gan
- School of Medicine, Huzhou University, Huzhou, China
| | - Quan Sun
- School of Medicine, Huzhou University, Huzhou, China
| | - Jiafang Yao
- Department of Cardiovascular Center, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Shengyi Lian
- Department of Cardiovascular Center, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - WenJuan Wang
- Department of Cardiovascular Center, First Affiliated Hospital of Huzhou University, Huzhou, China
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Monnens L. Weibel-Palade bodies: function and role in thrombotic thrombocytopenic purpura and in diarrhea phase of STEC-hemolytic uremic syndrome. Pediatr Nephrol 2025; 40:5-13. [PMID: 38967838 PMCID: PMC11584422 DOI: 10.1007/s00467-024-06440-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 06/01/2024] [Accepted: 06/12/2024] [Indexed: 07/06/2024]
Abstract
Vascular endothelial cells are equipped with numerous specialized granules called Weibel-Palade bodies (WPBs). They contain a cocktail of proteins that can be rapidly secreted (3-5 min) into the vascular lumen after an appropriate stimulus such as thrombin. These proteins are ready without synthesis. Von Willebrand factor (VWF) and P-selectin are the main constituents of WPBs. Upon stimulation, release of ultralarge VWF multimers occurs and assembles into VWF strings on the apical side of endothelium. The VWF A1 domain becomes exposed in a shear-dependent manner recruiting and activating platelets. VWF is able to recruit leukocytes via direct leukocyte binding or via the activated platelets promoting NETosis. Ultralarge VWF strings are ultimately cleaved into smaller pieces by the protease ADAMTS-13 preventing excessive platelet adhesion. Under carefully performed flowing conditions and adequate dose of Shiga toxins, the toxin induces the release of ultralarge VWF multimers from cultured endothelial cells. This basic information allows insight into the pathogenesis of thrombotic thrombocytopenic purpura (TTP) and of STEC-HUS in the diarrhea phase. In TTP, ADAMTS-13 activity is deficient and systemic aggregation of platelets will occur after a second trigger. In STEC-HUS, stimulated release of WPB components in the diarrhea phase of the disease can be presumed to be the first hit in the damage of Gb3 positive endothelial cells.
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Affiliation(s)
- Leo Monnens
- Department of Physiology, Radboud University Centre, Nijmegen, the Netherlands.
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Yao J, Zhang Y, Wang Z, Chen Y, Shi X. Maintenance of Cardiac Microenvironmental Homeostasis: A Joint Battle of Multiple Cells. J Cell Physiol 2025; 240:e31496. [PMID: 39632594 DOI: 10.1002/jcp.31496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/24/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024]
Abstract
Various cells such as cardiomyocytes, fibroblasts and endothelial cells constitute integral components of cardiac tissue. The health and stability of cardiac ecosystem are ensured by the action of a certain type of cell and the intricate interactions between multiple cell types. The dysfunctional cells exert a profound impact on the development of cardiovascular diseases by involving in the pathological process. In this paper, we introduce the dynamic activity, cell surface markers as well as biological function of the various cells in the heart. Besides, we discuss the multiple signaling pathways involved in the cardiac injury including Hippo/YAP, TGF-β/Smads, PI3K/Akt, and MAPK signaling. The complexity of different cell types poses a great challenge to the disease treatment. By characterizing the roles of various cell types in cardiovascular diseases, we sought to discuss the potential strategies for preventing and treating cardiovascular diseases.
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Affiliation(s)
- Jiayu Yao
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Youtao Zhang
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Ziwen Wang
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Yuejun Chen
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Xingjuan Shi
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
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Zheng L, Liu M, Gu X, Zhang Y, Wang Y. Efficacy and Safety of Aprocitentan in the Treatment of Hypertension: A Meta-Analysis of Evidence from Randomized Controlled Trials. Rev Cardiovasc Med 2025; 26:25909. [PMID: 39867183 PMCID: PMC11759960 DOI: 10.31083/rcm25909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/27/2024] [Accepted: 10/17/2024] [Indexed: 01/28/2025] Open
Abstract
Background Hypertension is one of the most prevalent disorders encountered in medical practice, yet effective pharmacotherapy options for resistant hypertension are limited. In this meta-analysis, we aimed to evaluate the efficacy and safety of aprocitentan in treating hypertension. Methods We searched PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library databases from inception to June 3, 2024, for randomized controlled trials (RCTs) that compared the efficacy and safety between aprocitentan and placebo in treating hypertension. According to the dosage of aprocitentan, the study was divided into a low-dose group (10-12.5 mg), medium-dose group (25 mg), and high-dose group (50 mg). Results This meta-analysis included five RCTs, which incorporated 1224 patients, and displayed that aprocitentan can reduce the mean sitting systolic blood pressure (msSBP) [(low dose subgroup: mean difference (MD): -3.85 mmHg; 95% confidence interval (CI): -7.47 to -0.23; p = 0.040; medium dose group: MD: -5.56 mmHg; 95% CI: -10.69 to -0.44; p = 0.030)], mean sitting diastolic blood pressure (msDBP) (low dose subgroup: MD: -3.95 mmHg; 95% CI: -4.06 to -3.85; p < 0.001; medium dose group: MD: -4.75 mmHg; 95% CI: -5.91 to -3.60; p < 0.001), 24-hour ambulatory systolic blood pressure (maSBP) (low dose group: MD: -4.18 mmHg; 95% CI: -4.32 to -4.04; p < 0.001; medium dose group: MD: -5.89 mmHg; 95% CI: -6.03 to -5.75; p < 0.001), and 24-hour ambulatory diastolic blood pressure (maDBP) (low dose group: MD: -4.33 mmHg; 95% CI: -4.42 to -4.24; p < 0.001; medium dose group: MD: -5.82 mmHg; 95% CI: -5.91 to -5.73; p < 0.001). In the high-dose group, there was no difference between the aprocitentan and placebo groups in the msSBP (MD: -4.83 mmHg; 95% CI: -11.44 to 1.79; p = 0.150). Meanwhile, the safety profile of aprocitentan was good, and no significant differences in the frequency of adverse events (AEs) and serious adverse events (SAEs) were observed compared to the placebo. Conclusions Aprocitentan significantly reduces blood pressure and has a good safety profile. However, it is worth noting that high doses of aprocitentan (50 mg) did not yield better blood pressure-lowering effects.
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Affiliation(s)
- Li Zheng
- Department of Pharmacy, China Aerospace Science & Industry Corporation 731 Hospital, 100074 Beijing, China
| | - Ming Liu
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, 730000 Lanzhou, Gansu, China
| | - Xiaotong Gu
- Department of Pharmacy, China Aerospace Science & Industry Corporation 731 Hospital, 100074 Beijing, China
| | - Yatong Zhang
- Department of Pharmacy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730 Beijing, China
| | - Yan Wang
- Department of Cardiovascular Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730 Beijing, China
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Empitu MA, Rinastiti P, Kadariswantiningsih IN. Targeting endothelin signaling in podocyte injury and diabetic nephropathy-diabetic kidney disease. J Nephrol 2025; 38:49-60. [PMID: 39302622 DOI: 10.1007/s40620-024-02072-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 08/08/2024] [Indexed: 09/22/2024]
Abstract
Despite advances in diabetes management, there is an urgent need for novel therapeutic strategies since the current treatments remain insufficient in halting the progression of diabetic nephropathy-diabetic kidney disease (DN-DKD). This review is mainly addressed on the pivotal role of endothelin-1 in the pathophysiology of DN, with a specific focus on its effects on podocytes and the glomerular filtration barrier. Endothelin-1 promotes mesangial cell proliferation, sclerosis, and direct podocyte injury via the activation of endothelin type A and B receptors, that drive the progression of glomerulosclerosis in DN-DKD. Endothelin receptor antagonists, including drugs like atrasentan and sparsentan, have demonstrated nephroprotective effects in experimental models by reducing proteinuria and podocyte injury. The therapeutic potential to slow the progression of DN to end-stage kidney disease (ESKD) of these endothelin receptor antagonists in clinical practice is currently under evaluation. However, fluid retention and increased risk of heart failure associated with endothelin receptor antagonists need careful consideration. This review aims to provide an in-depth analysis of the pathophysiological role of endothelin and the emerging therapeutic implications of targeting this pathway in DN-DKD and discusses efficacy, safety, and the possibility of combining the new generation of endothelin receptor antagonists with the standard treatment of CKD and DN-DKD.
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Affiliation(s)
- Maulana Antiyan Empitu
- Faculty of Medicine, Airlangga University, Surabaya, Indonesia
- Faculty of Health, Medicine and Natural Sciences (FIKKIA), Airlangga University, Banyuwangi, Indonesia
| | - Pranindya Rinastiti
- Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, Kobe, Japan
- Department of Clinical Pathology, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, Indonesia
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van Oostveen WM, Hoekstra EM, Levarht EWN, Kotliar IB, Sakmar TP, Toes REM, de Vries-Bouwstra JK, Heitman LH, Fehres CM. Absence of Functional Autoantibodies Targeting Angiotensin II Receptor Type 1 and Endothelin-1 Type A Receptor in Circulation and Purified IgG From Patients With Systemic Sclerosis. Arthritis Rheumatol 2024. [PMID: 39721751 DOI: 10.1002/art.43099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 12/03/2024] [Accepted: 12/11/2024] [Indexed: 12/28/2024]
Abstract
OBJECTIVE Systemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. Although previous studies have highlighted the presence of functional autoantibodies targeting the angiotensin II receptor type 1 (AT1) and endothelin-1 type A receptor (ETAR), leading to autoantibody-mediated receptor stimulation and subsequent activation of endothelial cells (ECs), a comprehensive understanding of the direct interaction between these autoantibodies and their receptors is currently lacking. Moreover, existing data confirming the presence of these autoantibodies in SSc often rely on similar methodologies and assays. Our aim was to replicate previous findings and to investigate the functional effects of IgG derived from patients with SSc (SSc IgG) on AT1 and ETAR signaling, the downstream EC response, and the presence of AT1-binding autoantibodies in circulation. METHODS Quantitative polymerase chain reaction and cytokine enzyme-linked immunosorbent assay, alongside a real-time cell analyzer, were used to assess receptor-specific functional characteristics of purified SSc IgG (n = 18). Additionally, a novel protein capture assay using solubilized epitope-tagged AT1 was developed to detect AT1-binding autoantibodies in plasma samples from patients with SSc (n = 28) and healthy donors (n = 14). RESULTS No evidence for EC activation in an AT1- or ETAR-dependent manner was revealed. Furthermore, stimulation with SSc IgG did not induce receptor activation or alter G protein-coupled receptor signaling on agonist stimulation in a model with receptor overexpression. Lastly, no AT1-binding autoantibodies were detected in plasma samples from patients with SSc when using epitope-tagged solubilized AT1. CONCLUSION Overall, our study did not provide evidence to support the presence of AT1- or ETAR-activating autoantibodies in purified SSc IgG or AT1-binding autoantibodies in the circulation of patients with SSc.
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Affiliation(s)
| | - Eva M Hoekstra
- Leiden University Medical Center, Leiden, The Netherlands
| | | | - Ilana B Kotliar
- The Rockefeller University and Tri-Institutional PhD Program in Chemical Biology, New York, New York
| | | | - René E M Toes
- Leiden University Medical Center, Leiden, The Netherlands
| | | | - Laura H Heitman
- Leiden University and Oncode Institute, Leiden, The Netherlands
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De Michele M, Amisano P, Schiavo OG, Cammisotto V, Carnevale R, Forte M, Picchio V, Ciacciarelli A, Berto I, Angeloni U, Pugliese S, Toni D, Lorenzano S. Secondary Brain Injury After Parenchymal Cerebral Hemorrhage in Humans: The Role of NOX2-Mediated Oxidative Stress and Endothelin-1. Int J Mol Sci 2024; 25:13180. [PMID: 39684890 DOI: 10.3390/ijms252313180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024] Open
Abstract
Perihematomal hypoperfusion may lead to ischemic damage during intraparenchymal cerebral hemorrhage (ICH), resulting in worse prognosis. We aimed to (1) investigate the relationship between serum biomarkers related to oxidative stress and vasoactive substances and the occurrence of hypoperfusion and ischemic perihematomal lesions in ICH and (2) evaluate their correlation with the volumetric evolution of the hematoma and perihematomal edema. We enrolled 28 patients affected by ICH. Blood samples were collected at three different time points from symptom onset: T0, T1, and T2 (admission, 12-24 h, and 48-72 h, respectively), to measure endothelin-1 (ET-1), nitrites/nitrates (NO), soluble nicotinamide adenine dinucleotide 2 (NOX2)-derived peptide (sNOX2-dp), and asymmetric dimethylarginine (ADMA). Patients underwent brain MRI with perfusion study at T1 and MRI without perfusion at T2. 12 patients had ischemic perihematomal lesions at T1. A higher sNOX2-dp concentration at T0 was observed in patients with ischemic perihematomal lesions compared to those without (p = 0.051) and with a more severe perihematomal edema at T2 (p = 0.011). The ischemic perihematomal lesions development was also associated with an increased hematoma volume (p < 0.005), perilesional edema (p = 0.046), and greater midline shift (p = 0.036). ET-1 values at T1 were inversely correlated with hemorrhage volume at T2 (ρ = -0.717, p = 0.030). NOX2 activation may have a role in the development of ischemic perihematomal lesions. The association between higher ET-1 values and a lower hemorrhage volume could be related to the ET-1 vasoconstriction action on the ruptured vessel wall.
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Affiliation(s)
- Manuela De Michele
- Stroke Unit, Umberto I Hospital, Emergency Department, Sapienza University, 00185 Rome, Italy
| | - Paolo Amisano
- Department of Human Neurosciences, Sapienza University, 00185 Rome, Italy
| | - Oscar G Schiavo
- Stroke Unit, Umberto I Hospital, Emergency Department, Sapienza University, 00185 Rome, Italy
| | - Vittoria Cammisotto
- Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University, 00185 Rome, Italy
| | - Roberto Carnevale
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University, 04100 Latina, Italy
- IRCCS Neuromed, 86077 Pozzilli, Italy
| | | | | | - Antonio Ciacciarelli
- Stroke Unit, Umberto I Hospital, Emergency Department, Sapienza University, 00185 Rome, Italy
| | - Irene Berto
- Stroke Unit, Umberto I Hospital, Emergency Department, Sapienza University, 00185 Rome, Italy
| | - Ugo Angeloni
- Neuroradiology Unit, Umberto I Hospital, Emergency Department, Sapienza University, 00185 Rome, Italy
| | - Silvia Pugliese
- Neuroradiology Unit, Umberto I Hospital, Emergency Department, Sapienza University, 00185 Rome, Italy
| | - Danilo Toni
- Department of Human Neurosciences, Sapienza University, 00185 Rome, Italy
| | - Svetlana Lorenzano
- Department of Human Neurosciences, Sapienza University, 00185 Rome, Italy
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Kühn J, Brandsch C, Bailer AC, Kiourtzidis M, Hirche F, Chen CY, Markó L, Bartolomaeus TUP, Löber U, Michel S, Wensch-Dorendorf M, Forslund-Startceva SK, Stangl GI. UV light exposure versus vitamin D supplementation: A comparison of health benefits and vitamin D metabolism in a pig model. J Nutr Biochem 2024; 134:109746. [PMID: 39178919 DOI: 10.1016/j.jnutbio.2024.109746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 08/26/2024]
Abstract
There is limited data on the effect of UV light exposure versus orally ingested vitamin D3 on vitamin D metabolism and health. A 4-week study with 16 pigs (as a model for human physiology) was conducted. The pigs were either supplemented with 20 µg/d vitamin D3 or exposed to UV light for 19 min/d to standardize plasma 25-hydroxyvitamin D3 levels. Important differences were higher levels of stored vitamin D3 in skin and subcutaneous fat, higher plasma concentrations of 3-epi-25-hydroxyvitamin D3 and increases of cutaneous lumisterol3 in UV-exposed pigs compared to supplemented pigs. UV light exposure compared to vitamin D3 supplementation resulted in lower hepatic cholesterol, higher circulating plasma nitrite, a marker of the blood pressure-lowering nitric oxide, and a reduction in the release of pro- and anti-inflammatory cytokines from stimulated peripheral blood mononuclear cells. However, plasma metabolome and stool microbiome analyses did not reveal any differences between the two groups. To conclude, the current data show important health relevant differences between oral vitamin D3 supplementation and UV light exposure. The findings may also partly explain the different vitamin D effects on health parameters obtained from association and intervention studies.
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Affiliation(s)
- Julia Kühn
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany.
| | - Corinna Brandsch
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
| | - Anja C Bailer
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany
| | - Mikis Kiourtzidis
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany
| | - Frank Hirche
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
| | - Chia-Yu Chen
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany; Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; DZHK, German Centre for Cardiovascular Research, Berlin, Germany
| | - Lajos Markó
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany; Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; DZHK, German Centre for Cardiovascular Research, Berlin, Germany
| | - Theda U P Bartolomaeus
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany; Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; DZHK, German Centre for Cardiovascular Research, Berlin, Germany
| | - Ulrike Löber
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany; Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; DZHK, German Centre for Cardiovascular Research, Berlin, Germany
| | - Samira Michel
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
| | - Monika Wensch-Dorendorf
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
| | - Sofia K Forslund-Startceva
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany; Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; DZHK, German Centre for Cardiovascular Research, Berlin, Germany; Structural and Computational Biology Unit, EMBL, Heidelberg, Germany
| | - Gabriele I Stangl
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany
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Asenjo-Bueno A, Alcalde-Estévez E, Olmos G, Martínez-Miguel P, Ruiz-Torres MP, López-Ongil S. Respiratory dysfunction in old mice could be related to inflammation and lung fibrosis induced by hyperphosphatemia. Eur J Clin Invest 2024; 54:e14302. [PMID: 39155424 DOI: 10.1111/eci.14302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 08/02/2024] [Indexed: 08/20/2024]
Abstract
BACKGROUND With age, lungs undergo typical changes that lead to a deterioration of respiratory function. Our aim was to assess the role of age-associated hyperphosphatemia in these changes. METHODS We used C57BL6 mice to study an ageing model in vivo and human lung fibroblasts were treated with a phosphate donor, beta-glycerophosphate (BGP), to explore mechanisms involved. Respiratory function was registered with a double chamber plethysmograph. Lung structure was analysed by different staining, phosphate and cytokines levels by colorimeric kits, expression of fibrosis, inflammation and ET-1 system by western blot or RT-PCR. RESULTS Old mice showed hyperphosphatemia, along with lung fibrosis, loss of elastin, increased expression of pro-inflammatory cytokines and impaired respiratory function. BGP induced inflammation and fibrosis in fibroblasts through the activation and binding of NFkB to the MCP-1 or FN promoters. BGP increased ECE-1 expression by inducing NFkB binding to the ECE-1 promoter. QNZ, an NFkB inhibitor, blocked these effects. When ECE-1 was inhibited with phosphoramidon, BGP-induced inflammation and fibrosis were significantly reduced, suggesting a role for ET-1 in BGP-mediated effects.ET-1 produced effects similar to those of BGP, which were also dependent on NFkB. To study the pathophysiological relevance of hyperphosphatemia in vivo, a low-P diet was administered to a group of old animals, showing an improvement in fibrosis, inflammation and respiratory function compared to old mice on a standard diet. CONCLUSION These results suggest that age-related hyperphosphatemia induces inflammation, fibrosis, and impaired respiratory function in old mice; these effects appear to be mediated by ET-1 and NFkB activation.
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Affiliation(s)
- Ana Asenjo-Bueno
- Departamento de Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
| | - Elena Alcalde-Estévez
- Departamento de Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
| | - Gemma Olmos
- Departamento de Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- Instituto Reina Sofía de Investigación Nefrológica (IRSIN) de la Fundación Renal Iñigo Álvarez de Toledo (FRIAT), Madrid, Spain
- Area 3-Fisiología y Fisiopatología Renal y Vascular del IRYCIS, Madrid, Spain
| | - Patricia Martínez-Miguel
- Servicio de Nefrología del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
| | - María Piedad Ruiz-Torres
- Departamento de Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- Instituto Reina Sofía de Investigación Nefrológica (IRSIN) de la Fundación Renal Iñigo Álvarez de Toledo (FRIAT), Madrid, Spain
- Area 3-Fisiología y Fisiopatología Renal y Vascular del IRYCIS, Madrid, Spain
| | - Susana López-Ongil
- Departamento de Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- Instituto Reina Sofía de Investigación Nefrológica (IRSIN) de la Fundación Renal Iñigo Álvarez de Toledo (FRIAT), Madrid, Spain
- Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
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Amiri Roudbar M, Rosengren MK, Mousavi SF, Fegraeus K, Naboulsi R, Meadows JRS, Lindgren G. Effect of an endothelial regulatory module on plasma proteomics in exercising horses. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2024; 52:101265. [PMID: 38906044 DOI: 10.1016/j.cbd.2024.101265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 06/04/2024] [Accepted: 06/04/2024] [Indexed: 06/23/2024]
Abstract
Elite performing exercise requires an intricate modulation of the blood pressure to support the working muscles with oxygen. We have previously identified a genomic regulatory module that associates with differences in blood pressures of importance for elite performance in racehorses. This study aimed to determine the effect of the regulatory module on the protein repertoire. We sampled plasma from 12 Coldblooded trotters divided into two endothelial regulatory module haplotype groups, a sub-elite performing haplotype (SPH) and an elite performing haplotype (EPH), each at rest and exercise. The haplotype groups and their interaction were interrogated in two analyses, i) individual paired ratio analysis for identifying differentially abundant proteins of exercise (DAPE) and interaction (DAPI) between haplotype and exercise, and ii) unpaired ratio analysis for identifying differentially abundant protein of haplotype (DAPH). The proteomics analyses revealed a widespread change in plasma protein content during exercise, with a decreased tendency in protein abundance that is mainly related to lung function, tissue fluids, metabolism, calcium ion pathway and cellular energy metabolism. Furthermore, we provide the first investigation of the proteome variation due to the interaction between exercise and related blood pressure haplotypes, which this difference was related to a faster switch to the lipoprotein and lipid metabolism during exercise for EPH. The molecular signatures identified in the present study contribute to an improved understanding of exercise-related blood pressure regulation.
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Affiliation(s)
- Mahmoud Amiri Roudbar
- Department of Animal Science, Safiabad-Dezful Agricultural and Natural Resources Research and Education Center, Agricultural Research, Education and Extension Organization (AREEO), Dezful 333, Iran.
| | - Maria K Rosengren
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
| | - Seyedeh Fatemeh Mousavi
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
| | - Kim Fegraeus
- Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Sweden.
| | - Rakan Naboulsi
- Department of Women's and Children's Health, Karolinska Institute, Tomtebodavägen 18A, Stockholm 17177, Sweden.
| | - Jennifer R S Meadows
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 75132 Uppsala, Sweden.
| | - Gabriella Lindgren
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden; Center for Animal Breeding and Genetics, Department of Biosystems, KU Leuven, 3001 Leuven, Belgium.
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Hallow KM, Greasley PJ, Heerspink HJL, Yu H. Kinetics of endothelin-1 and effect selective ET A antagonism on ET B activation: a mathematical modeling analysis. Front Pharmacol 2024; 15:1332388. [PMID: 39664514 PMCID: PMC11632605 DOI: 10.3389/fphar.2024.1332388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 10/28/2024] [Indexed: 12/13/2024] Open
Abstract
Introduction Endothelin-1 (ET-1) regulates renal and vascular function, but the clinical utility of selective ETA receptor antagonists has been limited due to associated fluid retention. The mechanisms underlying fluid retention remain poorly understood but could be a consequence of changes in ET-1 binding to the unantagonized ETB receptor, either through increased ET-1 or non-selective ETB. Methods A mathematical model of ET-1 kinetics was developed to quantify effects of ETA antagonist exposure and selectivity on concentrations of ET-1 and its complexes with ETA and ETB receptors. The model describes ET-1 production, tissue and plasma distribution, ETA and ETB receptor binding, and receptor-mediated clearance, and was calibrated and validated with human ET-1 infusion studies. Results The model confirmed the significant role of ETB in ET-1 clearance. By varying both drug ETA selectivity (Kib/Kia) and concentration over a wide range, simulations predicted that while selective ETA antagonist (selectivity >1) always decreased [ET1-ETA], the change in [ET1-ETB] was more complex. It increased up to 45% as drug concentrations approached and exceeded Kia, but the increase was diminished as drug concentration increased further and fell below baseline at high concentrations. The drug concentration required to cause a decrease in [ET1-ETB] was lower as ETA selectivity decreased. Discussion This is the first mechanistic mathematical model of ET-1 kinetics that describes receptor-mediated clearance, and the consequence of ETB blockade on ET-1 concentrations. It provides a useful tool that can coupled with experimental studies to quantitively understand and investigate this complex and dynamic system.
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Affiliation(s)
- K. Melissa Hallow
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, United States
- Department of Epidemiology and Biostatistics, University of Georgia, Athens, GA, United States
| | - Peter J. Greasley
- Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals, R&D, AstraZeneca, Gothenburg, Sweden
| | - Hiddo J. L. Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands
- The George Institute for Global Health, Sydney, Australia
| | - Hongtao Yu
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, United States
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Karakaya E, Abdul Y, Edwards J, Jamil S, Albayram O, Ergul A. Complex regulation of tau phosphorylation by the endothelin system in brain microvascular endothelial cells (BMVECs): link to barrier function. Clin Sci (Lond) 2024; 138:1329-1341. [PMID: 39356969 DOI: 10.1042/cs20240616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 10/04/2024]
Abstract
Endothelin-1 (ET-1), the most potent vasoconstrictor identified to date, contributes to cerebrovascular dysfunction. ET-1 levels in postmortem brain specimens from individuals diagnosed with Alzheimer's disease (AD) and related dementias (ADRD) were shown to be related to cerebral hypoxia and disease severity. ET-1-mediated vascular dysfunction and ensuing cognitive deficits have also been reported in experimental models of AD and ADRD. Moreover, studies also showed that ET-1 secreted from brain microvascular endothelial cells (BMVECs) can affect neurovascular unit integrity in an autocrine and paracrine manner. Vascular contributions to cognitive impairment and dementia (VCID) is a leading ADRD cause known to be free of neuronal tau pathology, a hallmark of AD. However, a recent study reported cytotoxic hyperphosphorylated tau (p-tau) accumulation, which fails to bind or stabilize microtubules in BMVECs in VCID. Thus, the study aimed to determine the impact of ET-1 on tau pathology, microtubule organization, and barrier function in BMVECs. Cells were stimulated with 1 μM ET-1 for 24 h in the presence/absence of ETA (BQ123; 20 μM) or ETB (BQ788; 20 μM) receptor antagonists. Cell lysates were assayed for an array of phosphorylation site-specific antibodies and microtubule organization/stabilization markers. ET-1 stimulation increased p-tau Thr231 but decreased p-tau Ser199, Ser262, Ser396, and Ser214 levels only in the presence of ETA or ETB antagonism. ET-1 also impaired barrier function in the presence of ETA antagonism. These novel findings suggest that (1) dysregulation of endothelial tau phosphorylation may contribute to cerebral microvascular dysfunction and (2) the ET system may be an early intervention target to prevent hyperphosphorylated tau-mediated disruption of BMVEC barrier function.
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Affiliation(s)
- Eda Karakaya
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A
- Ralph H. Johnson Veterans Affairs Health Care System, Charleston, SC, U.S.A
| | - Yasir Abdul
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A
- Ralph H. Johnson Veterans Affairs Health Care System, Charleston, SC, U.S.A
| | - Jazlyn Edwards
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A
| | - Sarah Jamil
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A
- Ralph H. Johnson Veterans Affairs Health Care System, Charleston, SC, U.S.A
| | - Onder Albayram
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A
- Department of Neurosciences, Medical University of South Carolina, Charleston, SC, U.S.A
| | - Adviye Ergul
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A
- Ralph H. Johnson Veterans Affairs Health Care System, Charleston, SC, U.S.A
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Pushpam M, Talukdar A, Anilkumar S, Maurya SK, Issac TG, Diwakar L. Recurrent endothelin-1 mediated vascular insult leads to cognitive impairment protected by trophic factor pleiotrophin. Exp Neurol 2024; 381:114938. [PMID: 39197707 DOI: 10.1016/j.expneurol.2024.114938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/12/2024] [Accepted: 08/24/2024] [Indexed: 09/01/2024]
Abstract
Vascular dementia (VaD) is a complex neurodegenerative condition, with cerebral small vessel dysfunctions as the central role in its pathogenesis. Given the lack of suitable animal models to study the disease pathogenesis, we developed a mouse model to closely emulate the clinical scenarios of recurrent transient ischemic attacks (TIAs) leading to VaD using vasoconstricting peptide Endothelin-1(ET-1). We observed that administration of ET-1 led to blood-brain barrier (BBB) disruption and detrimental changes in its components, such as endothelial cells and pericytes, along with neuronal loss and synaptic dysfunction, resulting in irreversible memory loss. Further, in our pursuit of understanding potential interventions, we co-administered pleiotrophin (PTN) alongside ET-1 injections. PTN exhibited remarkable efficacy in preserving vital components of the BBB, including endothelial cells and pericytes, thereby restoring BBB integrity, preventing neuronal loss, and enhancing memory function. Our findings give a valuable framework for understanding the detrimental effects of multiple TIAs on brain health and provide a useful animal model to explore VaD's underlying mechanisms further and pave the way for promising therapies.
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Affiliation(s)
- Mayank Pushpam
- Centre for Brain Research, Indian Institute of Science, Bangalore 560012, India; Manipal Academy of Higher Education (MAHE), Manipal 576104, India
| | - Ankita Talukdar
- Centre for Brain Research, Indian Institute of Science, Bangalore 560012, India
| | - Shobha Anilkumar
- Centre for Brain Research, Indian Institute of Science, Bangalore 560012, India
| | | | - Thomas Gregor Issac
- Centre for Brain Research, Indian Institute of Science, Bangalore 560012, India
| | - Latha Diwakar
- Centre for Brain Research, Indian Institute of Science, Bangalore 560012, India.
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Yu H, Greasley PJ, Lambers Heerspink HJ, Ambery P, Ahlstrom C, Hamren B, Khan AA, Boulton DW, Hallow KM. The role of venous capacity in fluid retention with endothelin A antagonism: Mathematical modelling of the RADAR trial. Br J Pharmacol 2024; 181:4693-4707. [PMID: 39159936 DOI: 10.1111/bph.16504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 05/17/2024] [Accepted: 06/10/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND AND PURPOSE Endothelin-1 (ET-1) receptor A (ETA) antagonists reduce proteinuria and prevent renal outcomes in chronic kidney disease (CKD) patients, but their utility has been limited because of associated fluid retention, resulting in increased heart failure risk. Understanding the mechanisms responsible for fluid retention could result in solutions that preserve renoprotective effects while mitigating fluid retention, but the complexity of the endothelin system has made identification of the underlying mechanisms challenging. APPROACH We utilized a previously developed mathematical model of ET-1 kinetics, ETA receptor antagonism, kidney function, haemodynamics, and sodium and water homeostasis to evaluate hypotheses for mechanisms of fluid retention with ETA antagonism. To do this, we simulated the RADAR clinical trial of atrasentan in patients with type 2 diabetes and CKD and evaluated the ability of the model to predict the observed decreases in haematocrit, urine albumin creatinine ratio (UACR), mean arterial pressure (MAP), and estimated glomerular filtration rate (eGFR). BACKGROUND AND KEY RESULTS An effect of ETA antagonism on venodilation and increased venous capacitance was found to be the critical mechanism necessary to reproduce the simultaneous decrease in both MAP and haematocrit observed in RADAR. CONCLUSIONS AND IMPACT These findings indicate that fluid retention with ETA antagonism may not be caused by a direct antidiuretic effect within the kidney but is instead be an adaptive response to venodilation and increased venous capacity, which acutely tends to reduce cardiac filling pressure and cardiac output, and that fluid retention occurs in an attempt to maintain cardiac filling and cardiac output.
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Affiliation(s)
- Hongtao Yu
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Peter J Greasley
- Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Hiddo J Lambers Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands
- The George Institute for Global Health, Sydney, Australia
| | - Philip Ambery
- Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Christine Ahlstrom
- Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Bengt Hamren
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Anis A Khan
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - David W Boulton
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - K Melissa Hallow
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia, USA
- Department of Epidemiology and Biostatistics, University of Georgia, Athens, Georgia, USA
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Gumanova NG, Vasilyev DK, Bogdanova NL, Drapkina OM. Serum Level of Cadherin-P (CDH3) Is a Novel Predictor of Cardiovascular Events Related to Atherosclerosis in a 3-Year Follow-Up Study. J Clin Med 2024; 13:6293. [PMID: 39518432 PMCID: PMC11546736 DOI: 10.3390/jcm13216293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/18/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024] Open
Abstract
Background: Placental cadherin (CDH3) is an adhesion molecule expressed in many malignant tumors. The role of serum CDH3 in atherosclerosis is unclear. Methods: This 3-year follow-up study measured atherosclerosis and serum CDH3 in 218 angiography inpatients. Coronary stenosis was assessed as the Gensini score. The brachiocephalic and femoral plaques were quantified by ultrasound. Microarray serum profiling was conducted in selected samples. CDH3 in the serum was measured using an indirect ELISA. The odds ratio (OR), ROC analysis, and logistic regressions were used to evaluate the associations between CDH3 content, atherosclerotic lesions, and various serum biomarkers. Results: Serum CDH3 was associated with the severity of atherosclerosis and diastolic blood pressure. The levels of CDH3 were able to discriminate patients with total subclinical and hemodynamically significant atherosclerotic lesions in all circulation pools (coronary, brachiocephalic, and femoral). Elevated serum CDH3 appeared to be a risk factor for cardiovascular outcomes after 3-year follow up with OR = 1.81 (95% CI: 1.07-3.72; p = 0.022). Endothelin-1 and NOx were associated with the content of CDH3 in the serum, suggesting the involvement of certain signal transduction pathways that may participate in plaque formation. Conclusions: CDH3 was associated with cardiovascular outcomes adjusted for coronary plaque presence, indicating a role of CDH3 in plaque biology.
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Affiliation(s)
- Nadezhda G. Gumanova
- Department of Biochemistry, National Research Center for Preventive Medicine (NRCPM), 101990 Moscow, Russia;
| | - Dmitry K. Vasilyev
- Department of Cardiovascular X-Ray Surgery, National Research Center for Preventive Medicine (NRCPM), 101990 Moscow, Russia;
| | - Natalya L. Bogdanova
- Department of Biochemistry, National Research Center for Preventive Medicine (NRCPM), 101990 Moscow, Russia;
| | - Oxana M. Drapkina
- Administrative Department, National Research Center for Preventive Medicine (NRCPM), 101990 Moscow, Russia;
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Peng X, Liu N, Zeng B, Bai Y, Xu Y, Chen Y, Chen L, Xia L. High salt diet accelerates skin aging in wistar rats: an 8-week investigation of cell cycle inhibitors, SASP markers, and oxidative stress. Front Bioeng Biotechnol 2024; 12:1450626. [PMID: 39465002 PMCID: PMC11502324 DOI: 10.3389/fbioe.2024.1450626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 09/27/2024] [Indexed: 10/29/2024] Open
Abstract
Background Recent studies have shown that the high salt diet (HSD) is linked to increased dermal pro-inflammatory status and reduced extracellular matrix (ECM) expression in inflamed skin of mice. Decreased ECM content is a known aging phenotype of the skin, and alterations in ECM composition and organization significantly contribute to skin aging. This study aimed to determine whether a high salt diet accelerates skin aging and to identify the time point at which this effect becomes apparent. Methods Wistar rats were randomly divided into normal diet and high salt diet groups and fed continuously for 8 weeks. Skin samples were collected at weeks 7 and week 8. Skin pathological sections were evaluated and levels of cell cycle inhibitors, senescence-associated secretory phenotype (SASP), oxidative stress and vascular regulatory factors (VRFs) were examined. Correlation analyses were performed to reveal the effect of a high salt diet as an extrinsic factor on skin aging and to analyse the correlation between a high salt diet and intrinsic aging and blood flow status. Results At week 8, HSD rats exhibited thickened epidermis, thinned dermis, and atrophied hair follicles. The expression of cell cycle inhibitors and oxidative stress levels were significantly elevated in the skin of HSD rats at both week 7 and week 8. At week 7, some SASPs, including TGF-β and PAI-1, were elevated, but others (IL-1, IL-6, IL-8, NO) were not significantly changed. By week 8, inflammatory molecules (IL-1, IL-6, TGF-β), chemokines (IL-8), proteases (PAI-1), and non-protein molecules (NO) were significantly increased. Notably, despite elevated PAI-1 levels suggesting possible blood hypercoagulation, the ET-1/NO ratio was reduced in the HSD group at week 8. Conclusion The data suggest that a high salt diet causes skin aging by week 8. The effect of a high salt diet on skin aging is related to the level of oxidative stress and the expression of cell cycle inhibitors. Additionally, a potential protective mechanism may be at play, as evidenced by the reduced ET-1/NO ratio, which could help counteract the hypercoagulable state and support nutrient delivery to aging skin.
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Affiliation(s)
- Xile Peng
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Administration of Traditional Chinese Medicine Key Laboratory of Traditional Chinese Medicine Regimen and Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Key Laboratory of Traditional Chinese Medicine Regimen and Health of Sichuan Province, Chengdu, China
| | - Nannan Liu
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Administration of Traditional Chinese Medicine Key Laboratory of Traditional Chinese Medicine Regimen and Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Key Laboratory of Traditional Chinese Medicine Regimen and Health of Sichuan Province, Chengdu, China
| | - Baihan Zeng
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Administration of Traditional Chinese Medicine Key Laboratory of Traditional Chinese Medicine Regimen and Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Key Laboratory of Traditional Chinese Medicine Regimen and Health of Sichuan Province, Chengdu, China
| | - Yilin Bai
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Administration of Traditional Chinese Medicine Key Laboratory of Traditional Chinese Medicine Regimen and Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Key Laboratory of Traditional Chinese Medicine Regimen and Health of Sichuan Province, Chengdu, China
| | - Yang Xu
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Administration of Traditional Chinese Medicine Key Laboratory of Traditional Chinese Medicine Regimen and Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Key Laboratory of Traditional Chinese Medicine Regimen and Health of Sichuan Province, Chengdu, China
| | - Yixiao Chen
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Administration of Traditional Chinese Medicine Key Laboratory of Traditional Chinese Medicine Regimen and Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Key Laboratory of Traditional Chinese Medicine Regimen and Health of Sichuan Province, Chengdu, China
| | - Li Chen
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Administration of Traditional Chinese Medicine Key Laboratory of Traditional Chinese Medicine Regimen and Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Key Laboratory of Traditional Chinese Medicine Regimen and Health of Sichuan Province, Chengdu, China
| | - Lina Xia
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Administration of Traditional Chinese Medicine Key Laboratory of Traditional Chinese Medicine Regimen and Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Key Laboratory of Traditional Chinese Medicine Regimen and Health of Sichuan Province, Chengdu, China
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Popa IP, Clim A, Pînzariu AC, Lazăr CI, Popa Ș, Tudorancea IM, Moscalu M, Șerban DN, Șerban IL, Costache-Enache II, Tudorancea I. Arterial Hypertension: Novel Pharmacological Targets and Future Perspectives. J Clin Med 2024; 13:5927. [PMID: 39407987 PMCID: PMC11478071 DOI: 10.3390/jcm13195927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 09/29/2024] [Accepted: 10/02/2024] [Indexed: 10/20/2024] Open
Abstract
Arterial hypertension (HTN) is one of the major global contributors to cardiovascular diseases and premature mortality, particularly due to its impact on vital organs and the coexistence of various comorbidities such as chronic renal disease, diabetes, cerebrovascular diseases, and obesity. Regardless of the accessibility of several well-established pharmacological treatments, the percentage of patients achieving adequate blood pressure (BP) control is still significantly lower than recommended levels. Therefore, the pharmacological and non-pharmacological management of HTN is currently the major focus of healthcare systems. Various strategies are being applied, such as the development of new pharmacological agents that target different underlying physiopathological mechanisms or associated comorbidities. Additionally, a novel group of interventional techniques has emerged in recent years, specifically for situations when blood pressure is not properly controlled despite the use of multiple antihypertensives in maximum doses or when patients are unable to tolerate or desire not to receive antihypertensive medications. Nonetheless, reducing the focus on antihypertensive medication development by the pharmaceutical industry and increasing recognition of ineffective HTN control due to poor drug adherence demands ongoing research into alternative approaches to treatment. The aim of this review is to summarize the potential novel pharmacological targets for the treatment of arterial hypertension as well as the future perspectives of the treatment strategy.
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Affiliation(s)
- Irene Paula Popa
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Andreea Clim
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Alin Constantin Pînzariu
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Cristina Iuliana Lazăr
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Ștefan Popa
- 2nd Department of Surgery–Pediatric Surgery and Orthopedics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Ivona Maria Tudorancea
- Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania
| | - Mihaela Moscalu
- Department of Preventive Medicine and Interdisciplinarity, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Dragomir N. Șerban
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Ionela Lăcrămioara Șerban
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Irina-Iuliana Costache-Enache
- Department of Internal Medicine I, Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania;
- Cardiology Clinic, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Ionuț Tudorancea
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
- Cardiology Clinic, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
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Rivera-Gonzalez O, Mills MF, Konadu BD, Wilson NA, Murphy HA, Newberry MK, Hyndman KA, Garrett MR, Webb DJ, Speed JS. Adipocyte endothelin B receptor activation inhibits adiponectin production and causes insulin resistance in obese mice. Acta Physiol (Oxf) 2024; 240:e14214. [PMID: 39096077 PMCID: PMC11421981 DOI: 10.1111/apha.14214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 08/04/2024]
Abstract
AIMS Endothelin-1 (ET-1) is elevated in patients with obesity and adipose tissue of obese mice fed high-fat diet (HFD); however, its contribution to the pathophysiology of obesity is not fully understood. Genetic loss of endothelin type B receptors (ETB) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ETB activation on adipocytes may contribute to obesity pathophysiology. We hypothesized that elevated ET-1 in obesity promotes insulin resistance by reducing the secretion of insulin sensitizing adipokines, via ETB receptor. METHODS Male adipocyte-specific ETB receptor knockout (adETBKO), overexpression (adETBOX), or control littermates were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks. RESULTS RNA-sequencing of epididymal adipose (eWAT) indicated differential expression of over 5500 genes (p < 0.05) in HFD compared to NMD controls, and changes in 1077 of these genes were attenuated in HFD adETBKO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adETBKO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adETBKO attenuated changes in plasma adiponectin, insulin, and leptin that is observed in HFD versus NMD control mice. Treatment of primary adipocytes with ET-1 caused a reduction in adiponectin production that was attenuated in cells pretreated with an ETB antagonist. CONCLUSION These data indicate elevated ET-1 in adipose tissue of mice fed HFD inhibits adiponectin production and causes insulin resistance through activation of the ETB receptor on adipocytes.
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Affiliation(s)
- Osvaldo Rivera-Gonzalez
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Megumi F. Mills
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Bridget D. Konadu
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Natalie A. Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Hayley A. Murphy
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Madison K. Newberry
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
| | - Kelly A. Hyndman
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham
| | - Michael R. Garrett
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216
| | - David J. Webb
- University/British Heart Foundation Centre for Cardiovascular Science|Queen’s Medical Research Institute, University of Edinburgh, UK
| | - Joshua S. Speed
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
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van Drie RWA, van de Wouw J, Zandbergen LM, Dehairs J, Swinnen JV, Mulder MT, Verhaar MC, MaassenVanDenBrink A, Duncker DJ, Sorop O, Merkus D. Vasodilator reactive oxygen species ameliorate perturbed myocardial oxygen delivery in exercising swine with multiple comorbidities. Basic Res Cardiol 2024; 119:869-887. [PMID: 38796544 PMCID: PMC11461570 DOI: 10.1007/s00395-024-01055-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/28/2024]
Abstract
Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ETA+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg-1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H2O2) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H2O2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ETA+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H2O2-mediated coronary vasodilation.
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Affiliation(s)
- R W A van Drie
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
- Laboratory of Vascular Medicine, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - J van de Wouw
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - L M Zandbergen
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
- Walter Brendel Center of Experimental Medicine (WBex), University Clinic Munich, 81377 LMU, Munich, Germany
| | - J Dehairs
- Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, Leuven, Belgium
| | - J V Swinnen
- Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, Leuven, Belgium
| | - M T Mulder
- Laboratory of Vascular Medicine, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - A MaassenVanDenBrink
- Laboratory of Vascular Medicine, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - D J Duncker
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - O Sorop
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - D Merkus
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
- Walter Brendel Center of Experimental Medicine (WBex), University Clinic Munich, 81377 LMU, Munich, Germany.
- Center for Cardiovascular Research (DZHK), Munich Heart Alliance (MHA), Partner Site Munich, 81377, Munich, Germany.
- Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICONLMU), University Clinic Munich, LMU, Munich, Germany.
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Pannucci P, Van Daele M, Cooper SL, Wragg ES, March J, Groenen M, Hill SJ, Woolard J. Role of endothelin ET A receptors in the hypertension induced by the VEGFR-2 kinase inhibitors axitinib and lenvatinib in conscious freely-moving rats. Biochem Pharmacol 2024; 228:116007. [PMID: 38145828 DOI: 10.1016/j.bcp.2023.116007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 12/27/2023]
Abstract
Receptor tyrosine kinase inhibitors (RTKIs) suppress tumour growth by targeting vascular endothelial growth factor receptor 2 (VEGFR-2) which is an important mediator of angiogenesis. Here, we demonstrate that two potent RTKIs, axitinib and lenvatinib, are associated with hypertensive side effects. Doppler flowmetry was used to evaluate regional haemodynamic profiles of axitinib and lenvatinib. Male Sprague Dawley rats (350-500 g) were instrumented with Doppler flow probes (renal and mesenteric arteries and descending abdominal aorta) and catheters (jugular vein and distal abdominal aorta, via the caudal artery). Rats were dosed daily with axitinib (3 or 6 mg.kg-1) or lenvatinib (1 or 3 mg.kg-1) and regional haemodynamics were recorded over a maximum of 4 days. Both RTKIs caused significant (p < 0.05) increases in mean arterial pressure (MAP), which was accompanied by significant (p < 0.05) vasoconstriction in both the mesenteric and hindquarters vascular beds. To gain insight into the involvement of endothelin-1 (ET-1) in RTKI-mediated hypertension, we also monitored heart rate (HR) and MAP in response to axitinib or lenvatinib in animals treated with the ETA receptor selective antagonist sitaxentan (5 mg.kg-1) or the mixed ETA/ETB receptor antagonist bosentan (15 mg.kg-1) over two days. Co-treatment with bosentan or sitaxentan markedly reduced the MAP effects mediated by both RTKIs (p < 0.05). Bosentan, but not sitaxentan, also attenuated ET-1 mediated increases in HR. These data suggest that selective antagonists of ETA receptors may be appropriate to alleviate the hypertensive effects of axitinib and lenvatinib.
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Affiliation(s)
- Patrizia Pannucci
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK
| | - Marieke Van Daele
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK
| | - Samantha L Cooper
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK
| | - Edward S Wragg
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK
| | - Julie March
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK
| | - Marleen Groenen
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK
| | - Stephen J Hill
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK.
| | - Jeanette Woolard
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK.
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