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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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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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Szymanska M, Basavaraja R, Meidan R. A tale of two endothelins: the rise and fall of the corpus luteum. Reprod Fertil Dev 2024; 37:RD24158. [PMID: 39680472 DOI: 10.1071/rd24158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Endothelins are small 21 amino acid peptides that interact with G-protein-coupled receptors. They are highly conserved across species and play important roles in vascular biology as well as in disease development and progression. Endothelins, mainly endothelin-1 and endothelin-2, are intricately involved in ovarian function and metabolism. These two peptides differ only in two amino acids but are encoded by different genes, which suggests an independent regulation and a cell-specific mode of expression. This review aims to comprehensively discuss the distinct regulation and roles of endothelin-1 and endothelin-2 regarding corpus luteum function throughout its life span.
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Affiliation(s)
- Magdalena Szymanska
- Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel; and Present address: Department of Hormonal Action Mechanisms, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Olsztyn, Poland
| | - Raghavendra Basavaraja
- Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel; and Present address: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Rina Meidan
- Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel
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Ham D, Shihoya W, Nureki O, Inoue A, Chung KY. Molecular mechanism of the endothelin receptor type B interactions with Gs, Gi, and Gq. Structure 2024; 32:1632-1639.e4. [PMID: 39043181 DOI: 10.1016/j.str.2024.06.020] [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: 04/11/2024] [Revised: 06/11/2024] [Accepted: 06/26/2024] [Indexed: 07/25/2024]
Abstract
The endothelin receptor type B (ETB) exhibits promiscuous coupling with various heterotrimeric G protein subtypes including Gs, Gi/o, Gq/11, and G12/13. Recent fluorescence and structural studies have raised questions regarding the coupling efficiencies and determinants of these G protein subtypes. Herein, by utilizing an integrative approach, combining hydrogen/deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cellular systems, we investigated conformational changes of Gs, Gi, and Gq triggered by ETB activation. ETB coupled to Gi and Gq but not with Gs. We underscored the critical roles of specific regions, including the C terminus of Gα and intracellular loop 2 (ICL2) of ETB in ETB-Gi1 or ETB-Gq coupling. Although The C terminus of Gα is essential for ETB-Gi1 and ETB-Gq coupling, ETB ICL2 influences Gq-coupling but not Gi1-coupling. Our results suggest a differential coupling efficiency of ETB with Gs, Gi1, and Gq, accompanied by distinct conformational changes in G proteins upon ETB-induced activation.
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MESH Headings
- Humans
- Binding Sites
- GTP-Binding Protein alpha Subunits, Gi-Go/metabolism
- GTP-Binding Protein alpha Subunits, Gi-Go/chemistry
- GTP-Binding Protein alpha Subunits, Gi-Go/genetics
- GTP-Binding Protein alpha Subunits, Gq-G11/metabolism
- GTP-Binding Protein alpha Subunits, Gq-G11/chemistry
- GTP-Binding Protein alpha Subunits, Gs/metabolism
- GTP-Binding Protein alpha Subunits, Gs/chemistry
- HEK293 Cells
- Models, Molecular
- Protein Binding
- Protein Conformation
- Receptor, Endothelin B/metabolism
- Receptor, Endothelin B/chemistry
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Affiliation(s)
- Donghee Ham
- School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
| | - Wataru Shihoya
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bumkyo-ku, Tokyo 113-0033, Japan
| | - Osamu Nureki
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bumkyo-ku, Tokyo 113-0033, Japan
| | - Asuka Inoue
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
| | - Ka Young Chung
- School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea.
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Moustakas D, Mani I, Pouliakis A, Iacovidou N, Xanthos T. The Effects of IRL-1620 in Post-ischemic Brain Injury: A Systematic Review and Meta-analysis of Experimental Studies. Neurocrit Care 2024; 41:665-680. [PMID: 38724864 DOI: 10.1007/s12028-024-01994-4] [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: 11/15/2023] [Accepted: 04/02/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND Sovateltide (IRL-1620), an endothelin B receptor agonist, has previously demonstrated neuroprotective and neuroregenerative effects in animal models of acute ischemic stroke. Recently, clinical trials indicated that it could also be effective in humans with stroke. Here, we systematically investigate whether IRL-1620 may be used for the treatment of ischemia-induced brain injury. METHODS A systematic review was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. MEDLINE (PubMed) and Scopus databases were searched for eligible studies up to December 2022. The databases ClinicalTrials.gov and Pharmazz Inc. were screened for unpublished or ongoing trials. Only studies in English were evaluated for eligibility. Meta-analysis of the included studies was also conducted. RESULTS Finally, seven studies were included in the review, all in animal rat models because of scarcity of clinical trials. Six studies, all in middle cerebral artery occlusion (MCAO) models, were selected for meta-analysis. In the two studies assessing mortality, no deaths were reported in the IRL-1620 group 24 h after MCAO, whereas the vehicle group had almost a five times higher mortality risk (risk ratio 5.3, 95% confidence interval 0.7-40.1, I2 = 0%). In all five studies evaluating outcome on day 7 after MCAO, IRL-1620 was associated with statistically significantly lower neurological deficit and improved motor performance compared with the vehicle. Infract volume, differentiation potential of neuronal progenitor cells, and mitochondrial fate also improved with IRL-1620 administration. CONCLUSIONS According to the above, in animal MCAO models, IRL-1620 enhanced neurogenesis and neuroprotection and improved outcome. Future studies are needed to expand our understanding of its effects in human study participants with acute ischemic stroke as well as in other common causes of cerebral ischemia including cardiac arrest.
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Affiliation(s)
- Dimitris Moustakas
- Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Iliana Mani
- 2d Department of Internal Medicine, Medical School, Hippokration General Hospital, National and Kapodistrian University of Athens, Vas. Sofias 114, 11527, Athens, Greece.
| | - Abraham Pouliakis
- 2d Department of Pathology, Attikon University General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikoletta Iacovidou
- Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Theodoros Xanthos
- School of Health Sciences, University of West Attica, Athens, Greece
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Patel M, Harris N, Kasztan M, Hyndman K. Comprehensive analysis of the endothelin system in the kidneys of mice, rats, and humans. Biosci Rep 2024; 44:BSR20240768. [PMID: 38904098 PMCID: PMC11249498 DOI: 10.1042/bsr20240768] [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: 06/18/2024] [Revised: 06/20/2024] [Accepted: 06/20/2024] [Indexed: 06/22/2024] Open
Abstract
The intrarenal endothelin (ET) system is an established moderator of kidney physiology and mechanistic contributor to the pathophysiology and progression of chronic kidney disease in humans and rodents. The aim of the present study was to characterize ET system by combining single cell RNA sequencing (scRNA-seq) data with immunolocalization in human and rodent kidneys of both sexes. Using publicly available scRNA-seq data, we assessed sex and kidney disease status (human), age and sex (rats), and diurnal expression (mice) on the kidney ET system expression. In normal human biopsies of both sexes and in rodent kidney samples, the endothelin-converting enzyme-1 (ECE1) and ET-1 were prominent in the glomeruli and endothelium. These data agreed with the scRNA-seq data from these three species, with ECE1/Ece1 mRNA enriched in the endothelium. However, the EDN1/Edn1 gene (encodes ET-1) was rarely detected, even though it was immunolocalized within the kidneys, and plasma and urinary ET-1 excretion are easily measured. Within each species, there were some sex-specific differences. For example, in kidney biopsies from living donors, men had a greater glomerular endothelial cell endothelin receptor B (Ednrb) compared with women. In mice, females had greater kidney endothelial cell Ednrb than male mice. As commercially available antibodies did not work in all species, and RNA expression did not always correlate with protein levels, multiple approaches should be considered to maintain required rigor and reproducibility of the pre- and clinical studies evaluating the intrarenal ET system.
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Affiliation(s)
- Margi Patel
- Department of Medicine, Division of Nephrology, Section of Cardio-Renal Physiology and Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, U.K
| | - Nicholas Harris
- Department of Medicine, Division of Nephrology, Section of Cardio-Renal Physiology and Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, U.K
| | - Malgorzata Kasztan
- Department of Pediatrics, Division of Hematology-Oncology, Section of Cardio-Renal Physiology and Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, U.K
| | - Kelly A. Hyndman
- Department of Medicine, Division of Nephrology, Section of Cardio-Renal Physiology and Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, U.K
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Otani M, Kushida Y, Kuroda Y, Wakao S, Oguma Y, Sasaki K, Katahira S, Terai R, Ryoke R, Nonaka H, Kawashima R, Saiki Y, Dezawa M. New rat model of spinal cord infarction with long-lasting functional disabilities generated by intraspinal injection of endothelin-1. Stroke Vasc Neurol 2024:svn-2023-002962. [PMID: 38906547 DOI: 10.1136/svn-2023-002962] [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: 11/04/2023] [Accepted: 06/04/2024] [Indexed: 06/23/2024] Open
Abstract
BACKGROUND The current method for generating an animal model of spinal cord (SC) infarction is highly invasive and permits only short-term observation, typically limited to 28 days. OBJECTIVE We aimed to establish a rat model characterised by long-term survival and enduring SC dysfunction by inducing selective ischaemic SC damage. METHODS In 8-week-old male Wistar rats, a convection-enhanced delivery technique was applied to selectively deliver endothelin-1 (ET-1) to the anterior horn of the SC at the Th13 level, leading to SC infarction. The Basso, Beattie and Bresnahan (BBB) locomotor score was assessed for 56 days. The SC was examined by a laser tissue blood flowmeter, MRI, immunohistochemistry, triphenyl tetrazolium chloride (TTC) staining, Western blots and TUNEL staining. RESULTS The puncture method was used to bilaterally inject 0.7 µL ET-1 (2.5 mg/mL) from the lateral SC into the anterior horns (40° angle, 1.5 mm depth) near the posterior root origin. Animals survived until day 56 and the BBB score was stably maintained (5.5±1.0 at day 14 and 6.2±1.0 at day 56). Rats with BBB scores ≤1 on day 1 showed stable scores of 5-6 after day 14 until day 56 while rats with BBB scores >1 on day 1 exhibited only minor dysfunction with BBB scores >12 after day 14. TTC staining, immunostaining and TUNEL staining revealed selective ischaemia and neuronal cell death in the anterior horn. T2-weighted MR images showed increasing signal intensity at the SC infarction site over time. Western blots revealed apoptosis and subsequent inflammation in SC tissue after ET-1 administration. CONCLUSIONS Selective delivery of ET-1 into the SC allows for more precise localisation of the infarcted area at the targeted site and generates a rat SC infarction model with stable neurological dysfunction lasting 56 days.
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Affiliation(s)
- Masayuki Otani
- Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yasumasa Kuroda
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yo Oguma
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Keisuke Sasaki
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Shintaro Katahira
- Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Ryohei Terai
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Rie Ryoke
- Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Miyagi, Japan
| | - Hiroi Nonaka
- Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Miyagi, Japan
| | - Ryuta Kawashima
- Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Miyagi, Japan
| | - Yoshikatsu Saiki
- Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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Lee JM, Jung HS. Putative role of endothelin receptor B in the development and maintenance of taste buds within the circumvallate papillae. J Oral Biosci 2024; 66:249-252. [PMID: 38220089 DOI: 10.1016/j.job.2024.01.005] [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: 12/15/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/16/2024]
Abstract
This study aimed to achieve a better understanding of taste receptor cell development relative to endothelin receptor B (ETB) in circumvallate papillae (CVP). ETB localization was assessed by immunohistochemistry during tongue development of the mouse. Co-localization of ETB with taste receptor type III cell marker, Synaptosomal-Associated Protein 25 kDa (SNAP25), was evident in both the developing and adult CVP. ETB was strongly localized in the stromal core region. As development progressed, ETB became localized in the CVP mesenchyme and partially in the epithelium. ETB and SNAP25 co-localization indicates that ETB may regulate innervation from the CVP mesenchyme to taste buds.
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Affiliation(s)
- Jong-Min Lee
- Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea
| | - Han-Sung Jung
- Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.
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Singh R, Singh V, Kumari P, Aggarwal N, Oberoi M, Khan H, Singh TG. Evolutionary Unmasking Resuscitative Therapeutics Potential of Centhaquin Citrate in Hypovolemic Shock. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:812-818. [PMID: 37357510 DOI: 10.2174/1871527322666230623113013] [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: 06/09/2022] [Revised: 04/22/2023] [Accepted: 05/05/2023] [Indexed: 06/27/2023]
Abstract
Hypovolemic shock (HS), a clinical condition of insufficient blood perfusion and oxygenation in body tissues, is associated with immense morbidity and mortality. Treatment approaches include fluid replacement and surgical repair of reversible causes of hemorrhage; however, they cause irreversible blood perfusion loss, systemic inflammation, multiple organ failure, and death. Centhaquin citrate (CC) is an innovative centrally acting cardiovascular active agent that is initially intended as an antihypertensive drug. However, due to its positive ionotropic effect, Centhaquin citrate is being tested clinically as a resuscitative agent for the management of hypovolemic shock It acts at the α2B-adrenergic receptor to produce venous constriction followed by an increase in venous return to the heart. These actions are assumed to be capable of resuscitative activity observed by centhaquin citrate, through an increase in cardiac output and tissue perfusion. Pharmacokinetics investigations in animals and humans have shown that centhaquin citrate is well tolerated and has insignificant side effects. Therefore, centhaquin citrate seems to be a promising entity and gaining the interest of researchers to develop it as a resuscitative agent in HS. The review gives insight into the development of centhaquin citrate as a resuscitative agent and provides insight into the associated mechanism of action and molecular signalling to foster future research on CC for its clinical use in HS.
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Affiliation(s)
- Ravinder Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Varinder Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Pratima Kumari
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Namita Aggarwal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Muskaan Oberoi
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Kanai SM, Clouthier DE. Endothelin signaling in development. Development 2023; 150:dev201786. [PMID: 38078652 PMCID: PMC10753589 DOI: 10.1242/dev.201786] [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] [Indexed: 12/18/2023]
Abstract
Since the discovery of endothelin 1 (EDN1) in 1988, the role of endothelin ligands and their receptors in the regulation of blood pressure in normal and disease states has been extensively studied. However, endothelin signaling also plays crucial roles in the development of neural crest cell-derived tissues. Mechanisms of endothelin action during neural crest cell maturation have been deciphered using a variety of in vivo and in vitro approaches, with these studies elucidating the basis of human syndromes involving developmental differences resulting from altered endothelin signaling. In this Review, we describe the endothelin pathway and its functions during the development of neural crest-derived tissues. We also summarize how dysregulated endothelin signaling causes developmental differences and how this knowledge may lead to potential treatments for individuals with gene variants in the endothelin pathway.
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Affiliation(s)
- Stanley M. Kanai
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - David E. Clouthier
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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11
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Rodas F, Vidal-Vidal JA, Herrera D, Brown-Brown DA, Vera D, Veliz J, Püschel P, Erices JI, Sánchez Hinojosa V, Tapia JC, Silva-Pavez E, Quezada-Monrás C, Mendoza-Soto P, Salazar-Onfray F, Carrasco C, Niechi I. Targeting the Endothelin-1 pathway to reduce invasion and chemoresistance in gallbladder cancer cells. Cancer Cell Int 2023; 23:318. [PMID: 38072958 PMCID: PMC10710704 DOI: 10.1186/s12935-023-03145-9] [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: 08/04/2023] [Accepted: 11/14/2023] [Indexed: 01/03/2025] Open
Abstract
BACKGROUND Gallbladder cancer (GBC) is a prevalent and deadly biliary tract carcinoma, often diagnosed at advanced stages with limited treatment options. The 5-year survival rate varies widely from 4 to 60%, mainly due to differences in disease stage detection. With only a small fraction of patients having resectable tumors and a high incidence of metastasis, advanced GBC stages are characterized by significant chemoresistance. Identification of new therapeutic targets is crucial, and recent studies have shown that the Endothelin-1 (ET-1) signaling pathway, involving ETAR and/or ETBR receptors (ETRs), plays a crucial role in promoting tumor aggressiveness in various cancer models. Blocking one or both receptors has been reported to reduce invasiveness and chemoresistance in cancers like ovarian, prostate, and colon. Furthermore, transcriptomic studies have associated ET-1 levels with late stages of GBC; however, it remains unclear whether its signaling or its inhibition has implications for its aggressiveness. Although the role of ET-1 signaling in gallbladder physiology is minimally understood, its significance in other tumor models leads us to hypothesize its involvement in GBC malignancy. RESULTS In this study, we investigated the expression of ET-1 pathway proteins in three GBC cell lines and a primary GBC culture. Our findings demonstrated that both ETAR and ETBR receptors are expressed in GBC cells and tumor samples. Moreover, we successfully down-regulated ET-1 signaling using a non-selective ETR antagonist, Macitentan, which resulted in reduced migratory and invasive capacities of GBC cells. Additionally, Macitentan treatment chemosensitized the cells to Gemcitabine, a commonly used therapy for GBC. CONCLUSION For the first time, we reveal the role of the ET-1 pathway in GBC cells, providing insight into the potential therapeutic targeting of its receptors to mitigate invasion and chemoresistance in this cancer with limited treatment options. These findings pave the way for further exploration of Macitentan or other ETR antagonists as potential therapeutic strategies for GBC management. In summary, our study represents a groundbreaking contribution to the field by providing the first evidence of the ET 1 pathway's pivotal role in modulating the behavior and aggressiveness of GBC cells, shedding new light on potential therapeutic targets.
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Affiliation(s)
- Francisco Rodas
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Jetzabel A Vidal-Vidal
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Daniela Herrera
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - David A Brown-Brown
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Diego Vera
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Joaquín Veliz
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Pilar Püschel
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - José I Erices
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Verónica Sánchez Hinojosa
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Julio C Tapia
- Laboratorio de transformación celular, Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453, Santiago, Chile
| | - Eduardo Silva-Pavez
- Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Bellavista, Santiago, Chile
| | - Claudia Quezada-Monrás
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
- Millennium Institute on Immunology and Immunotherapy, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Pablo Mendoza-Soto
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Flavio Salazar-Onfray
- Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, 8380453, Santiago, Chile
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, 8380453, Santiago, Chile
| | - Cristian Carrasco
- Subdepartamento de Anatomía Patológica, Hospital Base de Valdivia, 5090000, Valdivia, Chile
| | - Ignacio Niechi
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
- Millennium Institute on Immunology and Immunotherapy, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
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12
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Alarcon-Martinez L, Shiga Y, Villafranca-Baughman D, Cueva Vargas JL, Vidal Paredes IA, Quintero H, Fortune B, Danesh-Meyer H, Di Polo A. Neurovascular dysfunction in glaucoma. Prog Retin Eye Res 2023; 97:101217. [PMID: 37778617 DOI: 10.1016/j.preteyeres.2023.101217] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/23/2023] [Accepted: 09/25/2023] [Indexed: 10/03/2023]
Abstract
Retinal ganglion cells, the neurons that die in glaucoma, are endowed with a high metabolism requiring optimal provision of oxygen and nutrients to sustain their activity. The timely regulation of blood flow is, therefore, essential to supply firing neurons in active areas with the oxygen and glucose they need for energy. Many glaucoma patients suffer from vascular deficits including reduced blood flow, impaired autoregulation, neurovascular coupling dysfunction, and blood-retina/brain-barrier breakdown. These processes are tightly regulated by a community of cells known as the neurovascular unit comprising neurons, endothelial cells, pericytes, Müller cells, astrocytes, and microglia. In this review, the neurovascular unit takes center stage as we examine the ability of its members to regulate neurovascular interactions and how their function might be altered during glaucomatous stress. Pericytes receive special attention based on recent data demonstrating their key role in the regulation of neurovascular coupling in physiological and pathological conditions. Of particular interest is the discovery and characterization of tunneling nanotubes, thin actin-based conduits that connect distal pericytes, which play essential roles in the complex spatial and temporal distribution of blood within the retinal capillary network. We discuss cellular and molecular mechanisms of neurovascular interactions and their pathophysiological implications, while highlighting opportunities to develop strategies for vascular protection and regeneration to improve functional outcomes in glaucoma.
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Affiliation(s)
- Luis Alarcon-Martinez
- Department of Neuroscience, Université de Montréal, PO Box 6128, Station centre-ville, Montreal, QC, Canada; Neuroscience Division, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montreal, QC, Canada; Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia
| | - Yukihiro Shiga
- Department of Neuroscience, Université de Montréal, PO Box 6128, Station centre-ville, Montreal, QC, Canada; Neuroscience Division, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montreal, QC, Canada
| | - Deborah Villafranca-Baughman
- Department of Neuroscience, Université de Montréal, PO Box 6128, Station centre-ville, Montreal, QC, Canada; Neuroscience Division, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montreal, QC, Canada
| | - Jorge L Cueva Vargas
- Department of Neuroscience, Université de Montréal, PO Box 6128, Station centre-ville, Montreal, QC, Canada; Neuroscience Division, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montreal, QC, Canada
| | - Isaac A Vidal Paredes
- Department of Neuroscience, Université de Montréal, PO Box 6128, Station centre-ville, Montreal, QC, Canada; Neuroscience Division, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montreal, QC, Canada
| | - Heberto Quintero
- Department of Neuroscience, Université de Montréal, PO Box 6128, Station centre-ville, Montreal, QC, Canada; Neuroscience Division, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montreal, QC, Canada
| | - Brad Fortune
- Discoveries in Sight Research Laboratories, Devers Eye Institute and Legacy Research Institute, Legacy Healthy, Portland, OR, USA
| | - Helen Danesh-Meyer
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
| | - Adriana Di Polo
- Department of Neuroscience, Université de Montréal, PO Box 6128, Station centre-ville, Montreal, QC, Canada; Neuroscience Division, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montreal, QC, Canada.
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13
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Yegambaram M, Kumar S, Wu X, Lu Q, Sun X, Garcia Flores A, Meadows ML, Barman S, Fulton D, Wang T, Fineman JR, Black SM. Endothelin-1 acutely increases nitric oxide production via the calcineurin mediated dephosphorylation of Caveolin-1. Nitric Oxide 2023; 140-141:50-57. [PMID: 37659679 DOI: 10.1016/j.niox.2023.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 08/22/2023] [Accepted: 08/30/2023] [Indexed: 09/04/2023]
Abstract
Endothelin (ET)-1 is an endothelial-derived peptide that exerts biphasic effects on nitric oxide (NO) levels in endothelial cells such that acute exposure stimulates-while sustained exposure attenuates-NO production. Although the mechanism involved in the decrease in NO generation has been identified but the signaling involved in the acute increase in NO is still unresolved. This was the focus of this study. Our data indicate that exposing pulmonary arterial endothelial cells (PAEC) to ET-1 led to an increase in NO for up to 30min after which levels declined. These effects were attenuated by ET receptor antagonists. The increase in NO correlated with significant increases in pp60Src activity and increases in eNOS phosphorylation at Tyr83 and Ser1177. The ET-1 mediated increase in phosphorylation and NO generation were attenuated by the over-expression of a pp60Src dominant negative mutant. The increase in pp60Src activity correlated with a reduction in the interaction of Caveolin-1 with pp60Src and the calcineurin-mediated dephosphorylation of caveolin-1 at three previously unidentified sites: Thr91, Thr93, and Thr95. The calcineurin inhibitor, Tacrolimus, attenuated the acute increase in pp60Src activity induced by ET-1 and a calcineurin siRNA attenuated the ET-1 mediated increase in eNOS phosphorylation at Tyr83 and Ser1177 as well as the increase in NO. By using a Caveolin-1 celluSpot peptide array, we identified a peptide targeting a sequence located between aa 41-56 as the pp60Src binding region. This peptide fused to the TAT sequence was found to decrease caveolin-pp60Src interaction, increased pp60Src activity, increased eNOS pSer1177 and NO levels in PAEC and induce vasodilation in isolated aortic rings in wildtype but not eNOS knockout mice. Together, our data identify a novel mechanism by which ET-1 acutely increases NO via a calcineurin-mediated dephosphorylation of caveolin-1 and the subsequent stimulation of pp60Src activity, leading to increases in phosphorylation of eNOS at Tyr83 and Ser1177.
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Affiliation(s)
- Manivannan Yegambaram
- Center of Translational Science, Florida International University, Port St. Lucie, FL, 34987, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA
| | - Sanjiv Kumar
- Department of Medicine, Augusta University, Augusta, GA, USA; Vascular Biology Center, Augusta University, Augusta, GA, USA
| | - Xiaomin Wu
- Department of Medicine, University of Arizona, Tucson, AZ, 33174, USA
| | - Qing Lu
- Center of Translational Science, Florida International University, Port St. Lucie, FL, 34987, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA
| | - Xutong Sun
- Center of Translational Science, Florida International University, Port St. Lucie, FL, 34987, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA
| | - Alejandro Garcia Flores
- Center of Translational Science, Florida International University, Port St. Lucie, FL, 34987, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA
| | | | - Scott Barman
- Department of Pharmacology, Augusta University, Augusta, GA, USA
| | - David Fulton
- Vascular Biology Center, Augusta University, Augusta, GA, USA; Department of Pharmacology, Augusta University, Augusta, GA, USA
| | - Ting Wang
- Center of Translational Science, Florida International University, Port St. Lucie, FL, 34987, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA
| | - Jeffrey R Fineman
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Stephen M Black
- Center of Translational Science, Florida International University, Port St. Lucie, FL, 34987, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA; Department of Cellular Biology & Pharmacology, Howard Wertheim College of Medicine, Florida International University, Miami, FL, 33174, USA.
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14
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Shihoya W, Sano FK, Nureki O. Structural insights into endothelin receptor signalling. J Biochem 2023; 174:317-325. [PMID: 37491722 PMCID: PMC10533325 DOI: 10.1093/jb/mvad055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/19/2023] [Accepted: 07/01/2023] [Indexed: 07/27/2023] Open
Abstract
Endothelins and their receptors, type A (ETA) and type B (ETB), modulate vital cellular processes, including growth, survival, invasion and angiogenesis, through multiple G proteins. This review highlights the structural determinations of these receptors by X-ray crystallography and cryo-electron microscopy, and their activation mechanisms by endothelins. Explorations of the conformational changes upon receptor activation have provided insights into the unique G-protein coupling feature of the endothelin receptors. The review further delves into the binding modes of the clinical antagonist and the inverse agonists. These findings significantly contribute to understanding the mechanism of G-protein activation and have potential implications for drug development, particularly in the context of vasodilatory antagonists and agonists targeting the endothelin receptors.
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Affiliation(s)
- Wataru Shihoya
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
| | - Fumiya K Sano
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
| | - Osamu Nureki
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
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15
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Fato BR, Beard S, Binder NK, Pritchard N, Kaitu’u-Lino TJ, de Alwis N, Hannan NJ. The Regulation of Endothelin-1 in Pregnancies Complicated by Gestational Diabetes: Uncovering the Vascular Effects of Insulin. Biomedicines 2023; 11:2660. [PMID: 37893034 PMCID: PMC10603897 DOI: 10.3390/biomedicines11102660] [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: 08/10/2023] [Revised: 09/22/2023] [Accepted: 09/25/2023] [Indexed: 10/29/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is a condition of pregnancy defined by new-onset hyperglycemia. GDM is associated with impaired maternal endothelial and vascular reactivity. Endothelin-1 (ET-1) is a potent vasoconstrictor that contributes to endothelial dysfunction, however, its abundance and actions in GDM are unclear. Maternal plasma was obtained from pregnancies complicated by GDM (n = 24) and gestation-matched controls (n = 42); circulating ET-1 levels were assessed by ELISA. Human omental arteries from healthy pregnancies and those complicated by GDM were dissected from omental fat biopsies and collected at cesarean section. mRNA expression of ET-1 and its receptors, ETA and ETB, in addition to vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1) were assessed by qPCR (n = 28). Using wire myography, we investigated vascular constriction to ET-1 (10-11-10-4 M) in omental arteries from pregnancies complicated by GDM, compared to gestation-matched controls (n = 7). GDM cases were stratified by clinical management, diet intervention (n = 5), or insulin treatment (n = 6). Additionally, arteries from healthy pregnancies were treated with insulin (1 mU/mL (n = 7) and 10 mU/mL (n = 5)) or vehicle control. Vasoactive response to ET-1 was measured via wire myography. Circulating ET-1 levels and mRNA expression of the ET-1 system in omental arteries were not found to be significantly different between pregnancies complicated by GDM compared to healthy controls. However, we found insulin treatment during pregnancy and in ex vivo models reduced ET-1 vasoconstriction of maternal vasculature in GDM. These data suggest insulin may improve vascular function in GDM, however, further investigation is needed to define the role of ET-1 in pregnancy.
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Affiliation(s)
- Bianca R. Fato
- Therapeutics Discovery and Vascular Function in Pregnancy Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (B.R.F.); (S.B.); (N.K.B.); (N.d.A.)
- Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (N.P.); (T.J.K.-L.)
| | - Sally Beard
- Therapeutics Discovery and Vascular Function in Pregnancy Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (B.R.F.); (S.B.); (N.K.B.); (N.d.A.)
- Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (N.P.); (T.J.K.-L.)
| | - Natalie K. Binder
- Therapeutics Discovery and Vascular Function in Pregnancy Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (B.R.F.); (S.B.); (N.K.B.); (N.d.A.)
- Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (N.P.); (T.J.K.-L.)
| | - Natasha Pritchard
- Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (N.P.); (T.J.K.-L.)
| | - Tu’uhevaha J. Kaitu’u-Lino
- Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (N.P.); (T.J.K.-L.)
- Diagnostic Discovery and Reverse Translation in Pregnancy Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia
| | - Natasha de Alwis
- Therapeutics Discovery and Vascular Function in Pregnancy Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (B.R.F.); (S.B.); (N.K.B.); (N.d.A.)
- Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (N.P.); (T.J.K.-L.)
| | - Natalie J. Hannan
- Therapeutics Discovery and Vascular Function in Pregnancy Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (B.R.F.); (S.B.); (N.K.B.); (N.d.A.)
- Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, VIC 3084, Australia; (N.P.); (T.J.K.-L.)
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16
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Banecki KMRM, Dora KA. Endothelin-1 in Health and Disease. Int J Mol Sci 2023; 24:11295. [PMID: 37511055 PMCID: PMC10379484 DOI: 10.3390/ijms241411295] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Discovered almost 40 years ago, the potent vasoconstrictor peptide endothelin-1 (ET-1) has a wide range of roles both physiologically and pathologically. In recent years, there has been a focus on the contribution of ET-1 to disease. This has led to the development of various ET receptor antagonists, some of which are approved for the treatment of pulmonary arterial hypertension, while clinical trials for other diseases have been numerous yet, for the most part, unsuccessful. However, given the vast physiological impact of ET-1, it is both surprising and disappointing that therapeutics targeting the ET-1 pathway remain limited. Strategies aimed at the pathways influencing the synthesis and release of ET-1 could provide new therapeutic avenues, yet research using cultured cells in vitro has had little follow up in intact ex vivo and in vivo preparations. This article summarises what is currently known about the synthesis, storage and release of ET-1 as well as the role of ET-1 in several diseases including cardiovascular diseases, COVID-19 and chronic pain. Unravelling the ET-1 pathway and identifying therapeutic targets has the potential to treat many diseases whether through disease prevention, slowing disease progression or reversing pathology.
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Affiliation(s)
| | - Kim A Dora
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
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17
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Vallée A. Arterial stiffness and biological parameters: A decision tree machine learning application in hypertensive participants. PLoS One 2023; 18:e0288298. [PMID: 37418473 DOI: 10.1371/journal.pone.0288298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 06/23/2023] [Indexed: 07/09/2023] Open
Abstract
Arterial stiffness, measured by arterial stiffness index (ASI), could be considered a main denominator in target organ damage among hypertensive subjects. Currently, no reported ASI normal references have been reported. The index of arterial stiffness is evaluated by calculation of a stiffness index. Predicted ASI can be estimated regardless to age, sex, mean blood pressure, and heart rate, to compose an individual stiffness index [(measured ASI-predicted ASI)/predicted ASI]. A stiffness index greater than zero defines arterial stiffness. Thus, the purpose of this study was 1) to determine determinants of stiffness index 2) to perform threshold values to discriminate stiffness index and then 3) to determine hierarchical associations of the determinants by performing a decision tree model among hypertensive participants without CV diseases. A study was conducted from 53,363 healthy participants in the UK Biobank survey to determine predicted ASI. Stiffness index was applied on 49,452 hypertensives without CV diseases to discriminate determinants of positive stiffness index (N = 22,453) from negative index (N = 26,999). The input variables for the models were clinical and biological parameters. The independent classifiers were ranked from the most sensitives: HDL cholesterol≤1.425 mmol/L, smoking pack years≥9.2pack-years, Phosphate≥1.172 mmol/L, to the most specifics: Cystatin c≤0.901 mg/L, Triglycerides≥1.487 mmol/L, Urate≥291.9 μmol/L, ALT≥22.13 U/L, AST≤32.5 U/L, Albumin≤45.92 g/L, Testosterone≥5.181 nmol/L. A decision tree model was performed to determine rules to highlight the different hierarchization and interactions between these classifiers with a higher performance than multiple logistic regression (p<0.001). The stiffness index could be an integrator of CV risk factors and participate in future CV risk management evaluations for preventive strategies. Decision trees can provide accurate and useful classification for clinicians.
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Affiliation(s)
- Alexandre Vallée
- Department of Epidemiology and Public Health, Foch hospital, Suresnes, France
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18
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Yao Y, Fan B, Yang B, Jia Z, Li B. Aprocitentan: A new development of resistant hypertension. J Clin Hypertens (Greenwich) 2023. [PMID: 37334561 DOI: 10.1111/jch.14686] [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: 03/12/2023] [Revised: 05/29/2023] [Accepted: 05/30/2023] [Indexed: 06/20/2023]
Abstract
As the blood pressure threshold for commencing antihypertensive treatment diminishes, the cohort suffering from resistant hypertension (RH) correspondingly expands. Notwithstanding the availability of known antihypertensive medications, there exists a conspicuous lacuna in therapeutic options specifically intended for the management of RH. Currently, aprocitentan is the sole endothelin receptor antagonist (ERA) under development for addressing this pressing clinical challenge. Aprocitentan (ACT-132577), deriving its active form as a metabolite of macitentan, demonstrates oral potency as a dual endothelin (ET) receptor antagonist. This compound effectively obstructs the binding of endothelin-1 (ET-1) to both ETA and ETB receptors, exhibiting an inhibitory potency ratio of 1:16. Clinical investigation of aprocitentan has advanced to phase 3 trials, yielding promising preliminary outcomes.
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Affiliation(s)
- Yao Yao
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Shanxi Medical University, Taiyuan, Shanxi, China
| | - Bin Fan
- Shanxi Medical University, Taiyuan, Shanxi, China
| | - Bin Yang
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Zixuan Jia
- Shanxi Medical University, Taiyuan, Shanxi, China
| | - Bao Li
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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19
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Sano FK, Akasaka H, Shihoya W, Nureki O. Cryo-EM structure of the endothelin-1-ET B-G i complex. eLife 2023; 12:85821. [PMID: 37096326 PMCID: PMC10129325 DOI: 10.7554/elife.85821] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/23/2023] [Indexed: 04/26/2023] Open
Abstract
The endothelin ETB receptor is a promiscuous G-protein coupled receptor that is activated by vasoactive peptide endothelins. ETB signaling induces reactive astrocytes in the brain and vasorelaxation in vascular smooth muscle. Consequently, ETB agonists are expected to be drugs for neuroprotection and improved anti-tumor drug delivery. Here, we report the cryo-electron microscopy structure of the endothelin-1-ETB-Gi complex at 2.8 Å resolution, with complex assembly stabilized by a newly established method. Comparisons with the inactive ETB receptor structures revealed how endothelin-1 activates the ETB receptor. The NPxxY motif, essential for G-protein activation, is not conserved in ETB, resulting in a unique structural change upon G-protein activation. Compared with other GPCR-G-protein complexes, ETB binds Gi in the shallowest position, further expanding the diversity of G-protein binding modes. This structural information will facilitate the elucidation of G-protein activation and the rational design of ETB agonists.
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Affiliation(s)
- Fumiya K Sano
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Hiroaki Akasaka
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Wataru Shihoya
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Osamu Nureki
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
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20
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Briyal S, Ranjan AK, Gulati A. Oxidative stress: A target to treat Alzheimer's disease and stroke. Neurochem Int 2023; 165:105509. [PMID: 36907516 DOI: 10.1016/j.neuint.2023.105509] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 02/01/2023] [Accepted: 03/05/2023] [Indexed: 03/13/2023]
Abstract
Oxidative stress has been established as a well-known pathological condition in several neurovascular diseases. It starts with increased production of highly oxidizing free-radicals (e.g. reactive oxygen species; ROS and reactive nitrogen species; RNS) and becomes too high for the endogenous antioxidant system to neutralize them, which results in a significantly disturbed balance between free-radicals and antioxidants levels and causes cellular damage. A number of studies have evidently shown that oxidative stress plays a critical role in activating multiple cell signaling pathways implicated in both progression as well as initiation of neurological diseases. Therefore, oxidative stress continues to remain a key therapeutic target for neurological diseases. This review discusses the mechanisms involved in reactive oxygen species (ROS) generation in the brain, oxidative stress, and pathogenesis of neurological disorders such as stroke and Alzheimer's disease (AD) and the scope of antioxidant therapies for these disorders.
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Affiliation(s)
- Seema Briyal
- College of Pharmacy, Midwestern University, Downers Grove, IL, 60515, USA.
| | - Amaresh K Ranjan
- College of Pharmacy, Midwestern University, Downers Grove, IL, 60515, USA
| | - Anil Gulati
- College of Pharmacy, Midwestern University, Downers Grove, IL, 60515, USA; Pharmazz Inc. Research and Development, Willowbrook, IL, USA
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21
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Structural basis of peptide recognition and activation of endothelin receptors. Nat Commun 2023; 14:1268. [PMID: 36882417 PMCID: PMC9992518 DOI: 10.1038/s41467-023-36998-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 02/27/2023] [Indexed: 03/09/2023] Open
Abstract
Endothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), and two G protein-coupled receptor (GPCR) subtypes-endothelin receptor A (ETAR) and B (ETBR). Since ET-1, the first endothelin, was identified in 1988 as one of the most potent endothelial cell-derived vasoconstrictor peptides with long-lasting actions, the endothelin system has attracted extensive attention due to its critical role in vasoregulation and close relevance in cardiovascular-related diseases. Here we present three cryo-electron microscopy structures of ETAR and ETBR bound to ET-1 and ETBR bound to the selective peptide IRL1620. These structures reveal a highly conserved recognition mode of ET-1 and characterize the ligand selectivity by ETRs. They also present several conformation features of the active ETRs, thus revealing a specific activation mechanism. Together, these findings deepen our understanding of endothelin system regulation and offer an opportunity to design selective drugs targeting specific ETR subtypes.
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22
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Haroun R, Wood JN, Sikandar S. Mechanisms of cancer pain. FRONTIERS IN PAIN RESEARCH 2023; 3:1030899. [PMID: 36688083 PMCID: PMC9845956 DOI: 10.3389/fpain.2022.1030899] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 11/14/2022] [Indexed: 01/05/2023] Open
Abstract
Personalised and targeted interventions have revolutionised cancer treatment and dramatically improved survival rates in recent decades. Nonetheless, effective pain management remains a problem for patients diagnosed with cancer, who continue to suffer from the painful side effects of cancer itself, as well as treatments for the disease. This problem of cancer pain will continue to grow with an ageing population and the rapid advent of more effective therapeutics to treat the disease. Current pain management guidelines from the World Health Organisation are generalised for different pain severities, but fail to address the heterogeneity of mechanisms in patients with varying cancer types, stages of disease and treatment plans. Pain is the most common complaint leading to emergency unit visits by patients with cancer and over one-third of patients that have been diagnosed with cancer will experience under-treated pain. This review summarises preclinical models of cancer pain states, with a particular focus on cancer-induced bone pain and chemotherapy-associated pain. We provide an overview of how preclinical models can recapitulate aspects of pain and sensory dysfunction that is observed in patients with persistent cancer-induced bone pain or neuropathic pain following chemotherapy. Peripheral and central nervous system mechanisms of cancer pain are discussed, along with key cellular and molecular mediators that have been highlighted in animal models of cancer pain. These include interactions between neuronal cells, cancer cells and non-neuronal cells in the tumour microenvironment. Therapeutic targets beyond opioid-based management are reviewed for the treatment of cancer pain.
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Affiliation(s)
- Rayan Haroun
- Division of Medicine, Wolfson Institute of Biomedical Research, University College London, London, United Kingdom
| | - John N Wood
- Division of Medicine, Wolfson Institute of Biomedical Research, University College London, London, United Kingdom
| | - Shafaq Sikandar
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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23
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Endothelial and Vascular Smooth Muscle Dysfunction in Hypertension. Biochem Pharmacol 2022; 205:115263. [PMID: 36174768 DOI: 10.1016/j.bcp.2022.115263] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 12/11/2022]
Abstract
The development of essential hypertension involves several factors. Vascular dysfunction, characterized by endothelial dysfunction, low-grade inflammation and structural remodeling, plays an important role in the initiation and maintenance of essential hypertension. Although the mechanistic pathways by which essential hypertension develops are poorly understood, several pharmacological classes available on the clinical settings improve blood pressure by interfering in the cardiac output and/or vascular function. This review is divided in two major sections. The first section depicts the major molecular pathways as renin angiotensin aldosterone system (RAAS), endothelin, nitric oxide signalling pathway and oxidative stress in the development of vascular dysfunction. The second section describes the role of some pharmacological classes such as i) RAAS inhibitors, ii) dual angiotensin receptor-neprilysin inhibitors, iii) endothelin-1 receptor antagonists, iv) soluble guanylate cyclase modulators, v) phosphodiesterase type 5 inhibitors and vi) sodium-glucose cotransporter 2 inhibitors in the context of hypertension. Some classes are already approved in the treatment of hypertension, but others are not yet approved. However, due to their potential benefits these classes were included.
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24
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Fly casting with ligand sliding and orientational selection supporting complex formation of a GPCR and a middle sized flexible molecule. Sci Rep 2022; 12:13792. [PMID: 35963875 PMCID: PMC9376114 DOI: 10.1038/s41598-022-17920-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 08/02/2022] [Indexed: 11/08/2022] Open
Abstract
A GA-guided multidimensional virtual-system coupled molecular dynamics (GA-mD-VcMD) simulation was conducted to elucidate binding mechanisms of a middle-sized flexible molecule, bosentan, to a GPCR protein, human endothelin receptor type B (hETB). GA-mD-VcMD is a generalized ensemble method that produces a free-energy landscape of the ligand-receptor binding by searching large-scale motions accompanied with stable maintenance of the fragile cell-membrane structure. All molecular components (bosentan, hETB, membrane, and solvent) were represented with an all-atom model. Then sampling was conducted from conformations where bosentan was distant from the binding site in the hETB binding pocket. The deepest basin in the resultant free-energy landscape was assigned to native-like complex conformation. The following binding mechanism was inferred. First, bosentan fluctuating randomly in solution is captured using a tip region of the flexible N-terminal tail of hETB via nonspecific attractive interactions (fly casting). Bosentan then slides occasionally from the tip to the root of the N-terminal tail (ligand–sliding). During this sliding, bosentan passes the gate of the binding pocket from outside to inside of the pocket with an accompanying rapid reduction of the molecular orientational variety of bosentan (orientational selection). Last, in the pocket, ligand–receptor attractive native contacts are formed. Eventually, the native-like complex is completed. The bosentan-captured conformations by the tip-region and root-region of the N-terminal tail correspond to two basins in the free-energy landscape. The ligand-sliding corresponds to overcoming of a free-energy barrier between the basins.
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25
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Vallée A. Association between serum uric acid and arterial stiffness in a large-aged 40-70 years old population. J Clin Hypertens (Greenwich) 2022; 24:885-897. [PMID: 35748644 PMCID: PMC9278596 DOI: 10.1111/jch.14527] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/25/2022] [Accepted: 05/28/2022] [Indexed: 12/24/2022]
Abstract
Arterial stiffness (AS), measured by arterial stiffness index (ASI), is a determinant in cardiovascular (CV) diseases. A high serum uric acid (SUA) level is a known risk factor for CV disease. The authors investigated the relationship between SUA and ASI in the middle-age UK Biobank population study. AS was defined as ASI > 10 m/s. A cross-sectional study was conducted from 126 663 participants. Participants were divided into four quartiles according to SUA levels and sex. Sex multivariate analyses were performed with adjustment for confounding factors. The average ASI for overall participants was 9.3 m/s (SD: 2.9); 9.9 m/s (SD: 2.8) for men and 8.7 m/s (SD: 2.9) for women (P < .001). Men presented higher SUA rate (351.3 mmol/L (SD:67.9)) than women (270.7 mmol/L (SD:64.4)), P < .001. In men multivariate analysis, SUA remained a determinant of AS, with an increase in the strength of the association between the quartiles, Q4 versus Q1, OR = 1.10 [1.05-1.16], P < .001, Q3 versus Q1, OR = 1.09 [1.04-1.14], P < .001 but not between Q2 and Q1 (P = .136). In women, SUA remained significant for AS, with an increase in the strength of the association between the quartiles, Q4 versus Q1, OR = 1.22 [1.15-1.30], P < .001, Q3 versus Q1, OR = 1.13 [1.07-1.19], P < .001 and no difference between Q2 and Q1 (P = .101). When applying continuous SUA values in the multivariate analysis, SUA remained significant (P < .001), with a Youden index value for men = 338.3 mmol/L and for women = 267.3 mmol/L. High SUA levels were associated with AS, suggesting that SUA could be used as a predictor of atherosclerosis.
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Affiliation(s)
- Alexandre Vallée
- Department of Epidemiology-Data-Biostatistics, Delegation of Clinical Research and Innovation (DRCI), Foch hospital, Suresnes, France
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26
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Wang L, Wang L, Yan F. Understanding the molecular mechanism of endothelin ETA receptor selecting isopeptides endothelin-1 and -3. Biophys J 2022; 121:2490-2502. [DOI: 10.1016/j.bpj.2022.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 05/02/2022] [Accepted: 06/01/2022] [Indexed: 11/02/2022] Open
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Endothelin and the Cardiovascular System: The Long Journey and Where We Are Going. BIOLOGY 2022; 11:biology11050759. [PMID: 35625487 PMCID: PMC9138590 DOI: 10.3390/biology11050759] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022]
Abstract
Simple Summary In this review, we describe the basic functions of endothelin and related molecules, including their receptors and enzymes. Furthermore, we discuss the important role of endothelin in several cardiovascular diseases, the relevant clinical evidence for targeting the endothelin pathway, and the scope of endothelin-targeting treatments in the future. We highlight the present uses of endothelin receptor antagonists and the advancements in the development of future treatment options, thereby providing an overview of endothelin research over the years and its future scope. Abstract Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the endothelin system has been found to be critical in the pathogenesis of several cardiovascular diseases, including hypertension, pulmonary arterial hypertension, heart failure, and coronary artery disease. In this review, we summarize the current knowledge on endothelin and its role in cardiovascular diseases. Furthermore, we discuss how endothelin-targeting therapies, such as endothelin receptor antagonists, have been employed to treat cardiovascular diseases with varying degrees of success. Lastly, we provide a glimpse of what could be in store for endothelin-targeting treatment options for cardiovascular diseases in the future.
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Signaling cascades in the failing heart and emerging therapeutic strategies. Signal Transduct Target Ther 2022; 7:134. [PMID: 35461308 PMCID: PMC9035186 DOI: 10.1038/s41392-022-00972-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/13/2022] [Accepted: 03/20/2022] [Indexed: 12/11/2022] Open
Abstract
Chronic heart failure is the end stage of cardiac diseases. With a high prevalence and a high mortality rate worldwide, chronic heart failure is one of the heaviest health-related burdens. In addition to the standard neurohormonal blockade therapy, several medications have been developed for chronic heart failure treatment, but the population-wide improvement in chronic heart failure prognosis over time has been modest, and novel therapies are still needed. Mechanistic discovery and technical innovation are powerful driving forces for therapeutic development. On the one hand, the past decades have witnessed great progress in understanding the mechanism of chronic heart failure. It is now known that chronic heart failure is not only a matter involving cardiomyocytes. Instead, chronic heart failure involves numerous signaling pathways in noncardiomyocytes, including fibroblasts, immune cells, vascular cells, and lymphatic endothelial cells, and crosstalk among these cells. The complex regulatory network includes protein-protein, protein-RNA, and RNA-RNA interactions. These achievements in mechanistic studies provide novel insights for future therapeutic targets. On the other hand, with the development of modern biological techniques, targeting a protein pharmacologically is no longer the sole option for treating chronic heart failure. Gene therapy can directly manipulate the expression level of genes; gene editing techniques provide hope for curing hereditary cardiomyopathy; cell therapy aims to replace dysfunctional cardiomyocytes; and xenotransplantation may solve the problem of donor heart shortages. In this paper, we reviewed these two aspects in the field of failing heart signaling cascades and emerging therapeutic strategies based on modern biological techniques.
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Speck D, Kleinau G, Szczepek M, Kwiatkowski D, Catar R, Philippe A, Scheerer P. Angiotensin and Endothelin Receptor Structures With Implications for Signaling Regulation and Pharmacological Targeting. Front Endocrinol (Lausanne) 2022; 13:880002. [PMID: 35518926 PMCID: PMC9063481 DOI: 10.3389/fendo.2022.880002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 03/18/2022] [Indexed: 12/28/2022] Open
Abstract
In conjunction with the endothelin (ET) type A (ETAR) and type B (ETBR) receptors, angiotensin (AT) type 1 (AT1R) and type 2 (AT2R) receptors, are peptide-binding class A G-protein-coupled receptors (GPCRs) acting in a physiologically overlapping context. Angiotensin receptors (ATRs) are involved in regulating cell proliferation, as well as cardiovascular, renal, neurological, and endothelial functions. They are important therapeutic targets for several diseases or pathological conditions, such as hypertrophy, vascular inflammation, atherosclerosis, angiogenesis, and cancer. Endothelin receptors (ETRs) are expressed primarily in blood vessels, but also in the central nervous system or epithelial cells. They regulate blood pressure and cardiovascular homeostasis. Pathogenic conditions associated with ETR dysfunctions include cancer and pulmonary hypertension. While both receptor groups are activated by their respective peptide agonists, pathogenic autoantibodies (auto-Abs) can also activate the AT1R and ETAR accompanied by respective clinical conditions. To date, the exact mechanisms and differences in binding and receptor-activation mediated by auto-Abs as opposed to endogenous ligands are not well understood. Further, several questions regarding signaling regulation in these receptors remain open. In the last decade, several receptor structures in the apo- and ligand-bound states were determined with protein X-ray crystallography using conventional synchrotrons or X-ray Free-Electron Lasers (XFEL). These inactive and active complexes provide detailed information on ligand binding, signal induction or inhibition, as well as signal transduction, which is fundamental for understanding properties of different activity states. They are also supportive in the development of pharmacological strategies against dysfunctions at the receptors or in the associated signaling axis. Here, we summarize current structural information for the AT1R, AT2R, and ETBR to provide an improved molecular understanding.
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Affiliation(s)
- David Speck
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Berlin, Germany
| | - Gunnar Kleinau
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Berlin, Germany
| | - Michal Szczepek
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Berlin, Germany
| | - Dennis Kwiatkowski
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Berlin, Germany
| | - Rusan Catar
- Department of Nephrology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Aurélie Philippe
- Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Cardiovascular Research, Berlin, Germany
| | - Patrick Scheerer
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
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Kanai SM, Heffner C, Cox TC, Cunningham ML, Perez FA, Bauer AM, Reigan P, Carter C, Murray SA, Clouthier DE. Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants. Dis Model Mech 2022; 15:dmm049320. [PMID: 35284927 PMCID: PMC9066496 DOI: 10.1242/dmm.049320] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 02/22/2022] [Indexed: 12/16/2022] Open
Abstract
Auriculocondylar syndrome 2 (ARCND2) is a rare autosomal dominant craniofacial malformation syndrome linked to multiple genetic variants in the coding sequence of phospholipase C β4 (PLCB4). PLCB4 is a direct signaling effector of the endothelin receptor type A (EDNRA)-Gq/11 pathway, which establishes the identity of neural crest cells (NCCs) that form lower jaw and middle ear structures. However, the functional consequences of PLCB4 variants on EDNRA signaling is not known. Here, we show, using multiple signaling reporter assays, that known PLCB4 variants resulting from missense mutations exert a dominant-negative interference over EDNRA signaling. In addition, using CRISPR/Cas9, we find that F0 mouse embryos modeling one PLCB4 variant have facial defects recapitulating those observed in hypomorphic Ednra mouse models, including a bone that we identify as an atavistic change in the posterior palate/oral cavity. Remarkably, we have identified a similar osseous phenotype in a child with ARCND2. Our results identify the disease mechanism of ARCND2, demonstrate that the PLCB4 variants cause craniofacial differences and illustrate how minor changes in signaling within NCCs may have driven evolutionary changes in jaw structure and function. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Stanley M. Kanai
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | | | - Timothy C. Cox
- Departments of Oral and Craniofacial Sciences and Pediatrics, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Michael L. Cunningham
- University of Washington, Department of Pediatrics, Division of Craniofacial Medicine and Seattle Children's Craniofacial Center, Seattle, WA 98105, USA
| | - Francisco A. Perez
- University of Washington, Department of Radiology and Seattle Children's Hospital, Seattle, WA 98105, USA
| | - Aaron M. Bauer
- Department of Biology, Villanova University, Villanova, PA 19085, USA
| | - Philip Reigan
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Cristan Carter
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | | | - David E. Clouthier
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders. Int J Mol Sci 2022; 23:ijms23063146. [PMID: 35328566 PMCID: PMC8955091 DOI: 10.3390/ijms23063146] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 11/17/2022] Open
Abstract
Neurological/neurovascular disorders constitute the leading cause of disability and the second leading cause of death globally. Major neurological/neurovascular disorders or diseases include cerebral stroke, Alzheimer’s disease, spinal cord injury, neonatal hypoxic-ischemic encephalopathy, and others. Their pathophysiology is considered highly complex and is the main obstacle in developing any drugs for these diseases. In this review, we have described the endothelin system, its involvement in neurovascular disorders, the importance of endothelin B receptors (ETBRs) as a novel potential drug target, and its agonism by IRL-1620 (INN—sovateltide), which we are developing as a drug candidate for treating the above-mentioned neurological disorders/diseases. In addition, we have highlighted the results of our preclinical and clinical studies related to these diseases. The phase I safety and tolerability study of sovateltide has shown it as a safe and tolerable compound at therapeutic dosages. Furthermore, preclinical and clinical phase II studies have demonstrated the efficacy of sovateltide in treating acute ischemic stroke. It is under development as a first-in-class drug. In addition, efficacy studies in Alzheimer’s disease (AD), acute spinal cord injury, and neonatal hypoxic-ischemic encephalopathy (HIE) are ongoing. Successful completion of these studies will validate that ETBRs signaling can be an important target in developing drugs to treat neurological/neurovascular diseases.
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32
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Clozel M. Aprocitentan and the endothelin system in resistant hypertension. Can J Physiol Pharmacol 2022; 100:573-583. [PMID: 35245103 DOI: 10.1139/cjpp-2022-0010] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Endothelin has emerged as a target for therapeutic intervention in systemic hypertension. As a vasoconstrictor, co-mitogenic agent, linking pulse pressure and vascular remodeling, and mediator of aldosterone and catecholamine release, endothelin is a key player in hypertension and end-organ damage. In 10-20% of the hypertensive population, the high blood pressure is resistant to administration of antihypertensive drugs of different classes in combination. Because endothelin is not targeted by the current antihypertensive drugs this may suggest that this resistance is due, in part at least, to a dependence on endothelin. This hypothesis is supported by the observation that this form of hypertension is often salt-sensitive, and that the endothelin system is stimulated by salt. In addition, the endothelin system is activated in subjects at risk of developing resistant hypertension, such as African-Americans or patients with obesity or obstructive sleep apnea. Aprocitentan is a novel, potent, dual endothelin receptor antagonist (ERA) currently in phase 3 development for the treatment of difficult-to-treat hypertension. This article discusses the research which underpinned the discovery of this ERA and the choice of its first clinical indication for patients with forms of hypertension which cannot be well controlled with classical antihypertensive drugs.
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Affiliation(s)
- Martine Clozel
- Idorsia Pharmaceuticals Ltd, 510456, Allschwil, Basel-Landschaft, Switzerland;
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Qin C, Wang Y, Li S, Tang Y, Gao Y. The Involvement of Endothelin Pathway in Chronic Psychological Stress-Induced Bladder Hyperalgesia Through Capsaicin-Sensitive C-Fiber Afferents. J Inflamm Res 2022; 15:1209-1226. [PMID: 35228812 PMCID: PMC8882030 DOI: 10.2147/jir.s346855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 02/02/2022] [Indexed: 12/23/2022] Open
Abstract
Introductions Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood chronic disorder characterized by bladder-related pain. Chronic psychological stress plays a key role in the exacerbation and development of IC/BPS via unclear mechanisms. This study aimed to investigate the role of endothelin 1 (ET-1) and its receptors in the development of chronic stress-induced bladder dysfunction. Methods Wistar‐Kyoto rats were exposed to chronic (10 days) water avoidance stress (WAS) or sham stress, with subgroups receiving capsaicin pretreatment to desensitize C-fiber afferents. Thereafter, cystometrograms (CMG) were obtained with visceromotor response (VMR) simultaneously during intravesical saline or ET-1 infusion. CMG recordings were analyzed for the first and the continuous voiding cycles, respectively. Endothelin receptor type A (ETAR) expression was examined in the bladder tissues and L6-S1 dorsal root ganglions (DRGs). Toluidine blue staining was to check the bladder inflammation and double-labeling immunofluorescence (IF) staining was to identify the locations of ETAR, respectively. Results During saline infusion, WAS rats elicited significant decreases in pressure threshold (PT) and in the ratio of VMR threshold/maximum intravesical pressure (IVPmax), and a significant increase in VMR duration and area under the curve (AUC). ET-1 infusion induced similar alternations in WAS rats, but further significantly diminished the pressure to trigger PT and VMR, together with a more forceful and longer VMR. The sole effect of WAS exposure or ET-1 administration on the micturition reflex could be suppressed by capsaicin pretreatment. WAS exposure significantly induced an increased number of total mast cells in the bladder, while capsaicin pretreatment possibly antagonized them. No significant difference in ETAR expression was found between all groups. IF staining indicated the co-localization of ETAR and calcitonin gene-related peptides in both bladder and DRGs. Conclusion The activation of ET-1 receptors could enhance chronic stress-induced bladder hypersensitization and hyperalgesia through capsaicin-sensitive C-fiber afferents. Targeting the endothelin pathway may have therapeutic value for IC/BPS.
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Affiliation(s)
- Chuying Qin
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of China
| | - Yinhuai Wang
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of China
| | - Sai Li
- Acupuncture and Tuina School, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China
| | - Yuanyuan Tang
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of China
| | - Yunliang Gao
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of China
- Correspondence: Yunliang Gao, Department of Urology, The Second Xiangya Hospital, Central South University, No. 139. Renmin Road, Changsha, 410011, People’s Republic of China, Email
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Genovesi S, Giussani M, Orlando A, Lieti G, Viazzi F, Parati G. Relationship between endothelin and nitric oxide pathways in the onset and maintenance of hypertension in children and adolescents. Pediatr Nephrol 2022; 37:537-545. [PMID: 34085102 PMCID: PMC8921137 DOI: 10.1007/s00467-021-05144-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 05/03/2021] [Accepted: 05/17/2021] [Indexed: 02/07/2023]
Abstract
The mechanisms that regulate blood pressure are numerous and complex; one mechanism that plays an important role in this scenario is represented by the balance between the vasoconstrictor effect of endothelin-1 and the vasodilator effect of nitric oxide. While there is agreement on the fact that increased endothelin-1 activity and decreased nitric oxide bioavailability are present in hypertensive adults, the situation is less clear in children and adolescents. Not all studies agree on the finding of an increase in plasma endothelin-1 levels in hypertensive children and adolescents; in addition, the picture is often confused by the concomitant presence of obesity, a condition that stimulates the production of endothelin-1. Furthermore, there is recent evidence that, in younger obese and hypertensive subjects, there is an overproduction of nitric oxide, rather than a reduction. This condition may change over time, causing endothelial dysfunction due to a reduced availability of nitric oxide in hypertensive adolescents. The purpose of this review is to address the main biochemical and pathophysiological aspects of endothelin and nitric oxide involvement in hypertension and to summarize the available scientific evidence on their role in the onset and maintenance of high blood pressure in children and adolescents.
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Affiliation(s)
- Simonetta Genovesi
- School of Medicine and Surgery, University Milano - Bicocca, Milan, Italy. .,Department of Cardiovascular, Neural, and Metabolic Sciences, S Luca Hospital, IRCCS, Istituto Auxologico Italiano, Milan, Italy.
| | - Marco Giussani
- grid.418224.90000 0004 1757 9530Department of Cardiovascular, Neural, and Metabolic Sciences, S Luca Hospital, IRCCS, Istituto Auxologico Italiano, Milan, Italy
| | - Antonina Orlando
- grid.418224.90000 0004 1757 9530Department of Cardiovascular, Neural, and Metabolic Sciences, S Luca Hospital, IRCCS, Istituto Auxologico Italiano, Milan, Italy
| | - Giulia Lieti
- grid.7563.70000 0001 2174 1754School of Medicine and Surgery, University Milano - Bicocca, Milan, Italy
| | - Francesca Viazzi
- grid.410345.70000 0004 1756 7871Department of Internal Medicine, University of Study and IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Gianfranco Parati
- grid.7563.70000 0001 2174 1754School of Medicine and Surgery, University Milano - Bicocca, Milan, Italy ,grid.418224.90000 0004 1757 9530Department of Cardiovascular, Neural, and Metabolic Sciences, S Luca Hospital, IRCCS, Istituto Auxologico Italiano, Milan, Italy
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Toyama S, Tominaga M, Takamori K. Connections between Immune-Derived Mediators and Sensory Nerves for Itch Sensation. Int J Mol Sci 2021; 22:12365. [PMID: 34830245 PMCID: PMC8624544 DOI: 10.3390/ijms222212365] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/09/2021] [Accepted: 11/15/2021] [Indexed: 12/28/2022] Open
Abstract
Although histamine is a well-known itch mediator, histamine H1-receptor blockers often lack efficacy in chronic itch. Recent molecular and cellular based studies have shown that non-histaminergic mediators, such as proteases, neuropeptides and cytokines, along with their cognate receptors, are involved in evocation and modulation of itch sensation. Many of these molecules are produced and secreted by immune cells, which act on sensory nerve fibers distributed in the skin to cause itching and sensitization. This understanding of the connections between immune cell-derived mediators and sensory nerve fibers has led to the development of new treatments for itch. This review summarizes current knowledge of immune cell-derived itch mediators and neuronal response mechanisms, and discusses therapeutic agents that target these systems.
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Affiliation(s)
- Sumika Toyama
- Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Chiba 279-0021, Japan; (S.T.); (M.T.)
| | - Mitsutoshi Tominaga
- Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Chiba 279-0021, Japan; (S.T.); (M.T.)
- Anti-Aging Skin Research Laboratory, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Chiba 279-0021, Japan
| | - Kenji Takamori
- Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Chiba 279-0021, Japan; (S.T.); (M.T.)
- Anti-Aging Skin Research Laboratory, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Chiba 279-0021, Japan
- Department of Dermatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Chiba 279-0021, Japan
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Zangaladze A, Cai CL, Marcelino M, Aranda JV, Beharry KD. Renal biomarkers of acute kidney injury in response to increasing intermittent hypoxia episodes in the neonatal rat. BMC Nephrol 2021; 22:299. [PMID: 34481475 PMCID: PMC8418040 DOI: 10.1186/s12882-021-02507-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/19/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND We tested the hypotheses that: 1) early exposure to increasing episodes of clinically relevant intermittent hypoxia (IH) is detrimental to the developing kidneys; and 2) there is a critical number of daily IH episodes which will result in irreparable renal damage that may involve angiotensin (Ang) II and endothelin (ET)-1. METHODS At birth (P0), neonatal rat pups were exposed to brief IH episodes from the first day of life (P0) to P7 or from P0-P14. Pups were either euthanized immediately or placed in room air (RA) until P21. RA littermates served as controls. Kidneys were harvested at P7, P14, and P21 for histopathology; angiotensin converting enzyme (ACE), ACE-2, ET-1, big ET-1, and malondialdehyde (MDA) levels; immunoreactivity of ACE, ACE-2, ET-1, ET-2, ET receptors (ETAR, ETBR), and hypoxia inducible factor (HIF)1α; and apoptosis (TUNEL stain). RESULTS Histopathology showed increased renal damage with 8-12 IH episodes/day, and was associated with Ang II, ACE, HIF1α, and apoptosis. ACE-2 was not expressed at P7, and minimally increased at P14. However, a robust ACE-2 response was seen during recovery with maximum levels noted in the groups recovering from 8 IH episodes/day. ET-1, big ET-1, ETAR, ETBR, and MDA increased with increasing levels of neonatal IH. CONCLUSIONS Chronic neonatal IH causes severe damage to the developing kidney with associated elevations in vasoconstrictors, suggesting hypertension, particularly with 8 neonatal IH episodes. ACE-2 is not activated in early postnatal life, and this may contribute to IH-induced vasoconstriction. Therapeutic targeting of ACE and ET-1 may help decrease the risk for kidney injury in the developing neonate to prevent and/or treat neonatal acute kidney injury and/or chronic kidney disease.
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Affiliation(s)
- Anano Zangaladze
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
| | - Charles L Cai
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
| | - Matthew Marcelino
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
| | - Jacob V Aranda
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
- Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
- SUNY Eye Institute, New York, NY, USA
| | - Kay D Beharry
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA.
- Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA.
- SUNY Eye Institute, New York, NY, USA.
- Department of Pediatrics & Ophthalmology, Neonatal-Perinatal Medicine Clinical & Translational Research Labs, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Box 49, Brooklyn, NY, 11203, USA.
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Torres Crigna A, Link B, Samec M, Giordano FA, Kubatka P, Golubnitschaja O. Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine. EPMA J 2021; 12:265-305. [PMID: 34367381 PMCID: PMC8334338 DOI: 10.1007/s13167-021-00248-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
Endothelin-1 (ET-1) is involved in the regulation of a myriad of processes highly relevant for physical and mental well-being; female and male health; in the modulation of senses, pain, stress reactions and drug sensitivity as well as healing processes, amongst others. Shifted ET-1 homeostasis may influence and predict the development and progression of suboptimal health conditions, metabolic impairments with cascading complications, ageing and related pathologies, cardiovascular diseases, neurodegenerative pathologies, aggressive malignancies, modulating, therefore, individual outcomes of both non-communicable and infectious diseases such as COVID-19. This article provides an in-depth analysis of the involvement of ET-1 and related regulatory pathways in physiological and pathophysiological processes and estimates its capacity as a predictor of ageing and related pathologies,a sensor of lifestyle quality and progression of suboptimal health conditions to diseases for their targeted preventionand as a potent target for cost-effective treatments tailored to the person.
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Affiliation(s)
- Adriana Torres Crigna
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Barbara Link
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Frank A. Giordano
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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Shoemaker LN, Haigh KM, Kuczmarski AV, McGinty SJ, Welti LM, Hobson JC, Edwards DG, Feinberg RF, Wenner MM. ET B receptor-mediated vasodilation is regulated by estradiol in young women. Am J Physiol Heart Circ Physiol 2021; 321:H592-H598. [PMID: 34415188 DOI: 10.1152/ajpheart.00087.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The endothelin-B (ETB) receptor is a key regulator of vascular endothelial function in women. We have previously shown that the ETB receptor mediates vasodilation in young women, an effect that is lost after menopause. However, the direct impact of changes in estradiol (E2) on ETB receptor function in women remains unclear. Therefore, the purpose of this study was to test the hypothesis that E2 exposure modulates ETB receptor-mediated dilation in young women. Fifteen young women (24 ± 4 yr, 24 ± 3 kg/m2) completed the study. Endogenous sex hormone production was suppressed with daily administration of a gonadotropin-releasing hormone antagonist (GnRHant; Ganirelix) for 10 days; E2 (0.1 mg/day, Vivelle-Dot patch) was added back on days 4-10. We measured vasodilation in the cutaneous microcirculation (microvascular endothelial function) via local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant + E2) using laser Doppler flowmetry coupled with intradermal microdialysis during perfusions of lactated Ringer's (control) and ETB receptor antagonist (BQ-788, 300 nM). During GnRHant, vasodilatory responses to local heating were enhanced with ETB receptor blockade (control: 83 ± 9 vs. BQ-788: 90 ± 5%CVCmax, P = 0.004). E2 administration improved vasodilation in the control site (GnRHant: 83 ± 9 vs. GnRHant + E2: 89 ± 8%CVCmax, P = 0.036). Furthermore, cutaneous vasodilatory responses during ETB receptor blockade were blunted after E2 administration (control: 89 ± 8 vs. BQ-788: 84 ± 8%CVCmax, P = 0.047). These data demonstrate that ovarian hormones, specifically E2, modulate ETB receptor function and contribute to the regulation of microvascular endothelial function in young women.NEW & NOTEWORTHY The endothelin-B (ETB) receptor mediates vasodilation in young women, an effect lost following menopause. It is unclear whether these alterations are due to aging or changes in estradiol (E2). During endogenous hormone suppression (GnRH antagonist), blockade of ETB receptors enhanced cutaneous microvascular vasodilation. However, during E2 administration, blockade of ETB receptors attenuated vasodilation, indicating that the ETB receptor mediates dilation in the presence of E2. In young women, ETB receptors mediate vasodilation in the presence of E2, an effect that is lost when E2 is suppressed.
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Affiliation(s)
- Leena N Shoemaker
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
| | - Katherine M Haigh
- School of Nursing, University of Delaware, Newark, Delaware.,Reproductive Associates of Delaware, Newark, Delaware
| | - Andrew V Kuczmarski
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
| | - Shane J McGinty
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
| | - Laura M Welti
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
| | - Joshua C Hobson
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
| | - David G Edwards
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
| | | | - Megan M Wenner
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
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Riengvirodkij N, Roytrakul S, Jaresitthikunchai J, Phaonakrop N, Charoenlappanich S, Sakcamduang W. Peptide barcodes in dogs affected by mitral valve disease with and without pulmonary hypertension using MALDI-TOF MS and LC-MS/MS. PLoS One 2021; 16:e0255611. [PMID: 34383793 PMCID: PMC8360550 DOI: 10.1371/journal.pone.0255611] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 07/19/2021] [Indexed: 11/20/2022] Open
Abstract
Mitral valve disease (MVD) is an important and most frequently acquired heart disease found in dogs. MVD is classified into different stages according to its severity. There is a challenge in differentiation between asymptomatic and symptomatic stages of the MVD. Moreover, pulmonary hypertension (PH) is a common complication in dogs affected by MVD. In clinical practice, there are also some limitations to identify PH. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a technique that can characterize specific patterns of peptide mass called peptide barcodes from various samples. Besides, in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS), potential peptide sequences associated with specific conditions could be identified. The present study aimed to use MALDI-TOF coupled with LC-MS/MS to characterize specific peptide barcodes and potential peptide candidates in serum samples from healthy dogs, dogs with MVD stage B (MVD B, asymptomatic stage), MVD stage C (MVD C, symptomatic stage), MVD stage B with PH (MVD B PH), and MVD stage C with PH (MVD C PH). Discrete clusters of the 5 sample groups were identified by 3D plot analysis. Peptide barcodes also revealed differences in peptide patterns among the 5 groups. Six amino acid sequences of peptide candidates at 1,225.60, 1,363.85, 1,688.71, 1789.52, 2020.21, and 2156.42 Da were identified as part of the proteins CLCN1, CLUL1, EDNRA, PTEN, SLC39A7, and CLN6, respectively. The network interactions between these discovered proteins and common cardiovascular drugs were also investigated. These results demonstrate that MALDI-TOF MS has promise as an optional technique for diagnosing dogs affected by asymptomatic and symptomatic stages of MVD with and without PH. Further studies are required to identify peptide barcodes in dogs with other diseases to create peptide barcode databases in veterinary medicine before using this method as a novel diagnostic tool in the future.
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Affiliation(s)
- Nattapon Riengvirodkij
- Prasu-Arthorn Animal Hospital, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
| | - Sittiruk Roytrakul
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Janthima Jaresitthikunchai
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Narumon Phaonakrop
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Sawanya Charoenlappanich
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Walasinee Sakcamduang
- Department of Clinical Sciences and Public Health, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
- * E-mail:
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Fabik J, Psutkova V, Machon O. The Mandibular and Hyoid Arches-From Molecular Patterning to Shaping Bone and Cartilage. Int J Mol Sci 2021; 22:7529. [PMID: 34299147 PMCID: PMC8303155 DOI: 10.3390/ijms22147529] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/02/2021] [Accepted: 07/05/2021] [Indexed: 12/16/2022] Open
Abstract
The mandibular and hyoid arches collectively make up the facial skeleton, also known as the viscerocranium. Although all three germ layers come together to assemble the pharyngeal arches, the majority of tissue within viscerocranial skeletal components differentiates from the neural crest. Since nearly one third of all birth defects in humans affect the craniofacial region, it is important to understand how signalling pathways and transcription factors govern the embryogenesis and skeletogenesis of the viscerocranium. This review focuses on mouse and zebrafish models of craniofacial development. We highlight gene regulatory networks directing the patterning and osteochondrogenesis of the mandibular and hyoid arches that are actually conserved among all gnathostomes. The first part of this review describes the anatomy and development of mandibular and hyoid arches in both species. The second part analyses cell signalling and transcription factors that ensure the specificity of individual structures along the anatomical axes. The third part discusses the genes and molecules that control the formation of bone and cartilage within mandibular and hyoid arches and how dysregulation of molecular signalling influences the development of skeletal components of the viscerocranium. In conclusion, we notice that mandibular malformations in humans and mice often co-occur with hyoid malformations and pinpoint the similar molecular machinery controlling the development of mandibular and hyoid arches.
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Affiliation(s)
- Jaroslav Fabik
- Department of Developmental Biology, Institute of Experimental Medicine of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.F.); (V.P.)
- Department of Cell Biology, Faculty of Science, Charles University, 12800 Prague, Czech Republic
| | - Viktorie Psutkova
- Department of Developmental Biology, Institute of Experimental Medicine of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.F.); (V.P.)
- Department of Cell Biology, Faculty of Science, Charles University, 12800 Prague, Czech Republic
| | - Ondrej Machon
- Department of Developmental Biology, Institute of Experimental Medicine of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.F.); (V.P.)
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Siao AC, Shih LJ, Lin YY, Tsuei YW, Kuo YC, Ku HC, Chuu CP, Hsiao PJ, Kao YH. Investigation of the Molecular Mechanisms by Which Endothelin-3 Stimulates Preadipocyte Growth. Front Endocrinol (Lausanne) 2021; 12:661828. [PMID: 34093437 PMCID: PMC8176213 DOI: 10.3389/fendo.2021.661828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/12/2021] [Indexed: 11/13/2022] Open
Abstract
Endothelins induce many biological responses, and they are composed of three peptides: ET-1, ET-2, and ET-3. Reports have indicated that ET-1 regulates cell proliferation, adipogenesis, and other cell responses and that ET-3 stimulates the growth of gastrointestinal epithelial cells and melanocytes. However, the signalling pathways of ET3 that mediate the growth of fat cells are still unclear. Using 3T3-L1 white preadipocytes, we found that ET-3 induced increases in both cell number and BrdU incorporation. Pretreatment with an ETAR antagonist (but not an ETBR antagonist) blocked the ET-3-induced increases in both cell number and BrdU incorporation. Additionally, BQ610 suppressed the ET-3-induced increases in phosphorylation of AMPK, c-JUN, and STAT3 proteins, and pretreatment with specific inhibitors of AMPK, JNK/c-JUN, or JAK/STAT3 prevented the ET-3-induced increases in phosphorylation of AMPK, c-JUN, and STAT3, respectively. Neither p38 MAPK inhibitor nor PKC inhibitor altered the effects of ET-3 on cell growth. These data suggest that ET-3 stimulates preadipocyte growth through the ETAR, AMPK, JNK/c-JUN, and STAT3 pathways. Moreover, ET-3 did not alter HIB1B brown preadipocyte and D12 beige preadipocyte growth, suggesting a preadipocyte type-dependent effect. The results of this study may help explain how endothelin mediates fat cell activity and fat cell-associated diseases.
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Affiliation(s)
- An-Ci Siao
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Li-Jane Shih
- Medical Laboratory, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
- Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
| | - Yen-Yue Lin
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
- Department of Emergency Medicine, Taoyuan Armed Forces General Hospital, Taoyuan City, Taiwan
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Wei Tsuei
- Department of Emergency Medicine, Taoyuan Armed Forces General Hospital, Taoyuan City, Taiwan
| | - Yow-Chii Kuo
- Department of Gastroenterology, Landseed Hospital, Taoyuan, Taiwan
| | - Hui-Chen Ku
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Chih-Ping Chuu
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Po-Jen Hsiao
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan City, Taiwan
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yung-Hsi Kao
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
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The Role of Oxidative Stress in Hyperuricemia and Xanthine Oxidoreductase (XOR) Inhibitors. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1470380. [PMID: 33854690 PMCID: PMC8019370 DOI: 10.1155/2021/1470380] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 03/05/2021] [Accepted: 03/12/2021] [Indexed: 12/19/2022]
Abstract
Uric acid is the end product of purine metabolism in humans. Hyperuricemia is a metabolic disease caused by the increased formation or reduced excretion of serum uric acid (SUA). Alterations in SUA homeostasis have been linked to a number of diseases, and hyperuricemia is the major etiologic factor of gout and has been correlated with metabolic syndrome, cardiovascular disease, diabetes, hypertension, and renal disease. Oxidative stress is usually defined as an imbalance between free radicals and antioxidants in our body and is considered to be one of the main causes of cell damage and the development of disease. Studies have demonstrated that hyperuricemia is closely related to the generation of reactive oxygen species (ROS). In the human body, xanthine oxidoreductase (XOR) catalyzes the oxidative hydroxylation of hypoxanthine to xanthine to uric acid, with the accompanying production of ROS. Therefore, XOR is considered a drug target for the treatment of hyperuricemia and gout. In this review, we discuss the mechanisms of uric acid transport and the development of hyperuricemia, emphasizing the role of oxidative stress in the occurrence and development of hyperuricemia. We also summarize recent advances and new discoveries in XOR inhibitors.
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Abstract
PURPOSE OF REVIEW Inflammation has been shown to be an important factor in the development and progression of heart failure (HF), regardless of the etiology. There have been many studies that demonstrated roles of inflammatory biomarkers in diagnosis, prognosis of chronic and acute HF patients, and also markers of cardiotoxicity from chemotherapy. These cytokines are high-sensitivity C-reactive protein (hsCRP), myeloperoxidase (MPO), soluble growth stimulation expressed gene 2 (sST2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), growth differentiation factor-15 (GDF-15), endothelin-1 (ET-1), and galectin-3. In this review, we discuss the past and present insights of those inflammatory biomarkers in order to gain more understanding in pathogenesis of HF, risk stratification of HF patients, and early detection of cardiotoxicity from cancer therapy. RECENT FINDINGS Many inflammatory cytokines have been shown to be associated with mortality of both chronic and acute HF patients, and some of them are able to track treatment responses, especially sST2 and galectin-3, which are the only two inflammatory biomarkers recommended to use in clinical setting by the recent standard HF guidelines, while some studies described ET-1 and MPO as potential predictors of cardiotoxicity from cancer drugs. The prognostic implications of inflammatory biomarkers in HF patients have been demonstrated more consistently in chronic than acute HF, with some suggestions of ET-1 and MPO in patients receiving chemotherapy. However, further studies are necessary for the use of inflammatory biomarkers in routine clinical practice.
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Affiliation(s)
- Thanat Chaikijurajai
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH, 44195, USA
- Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - W H Wilson Tang
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH, 44195, USA.
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Endoglin in the Spotlight to Treat Cancer. Int J Mol Sci 2021; 22:ijms22063186. [PMID: 33804796 PMCID: PMC8003971 DOI: 10.3390/ijms22063186] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/06/2021] [Accepted: 03/17/2021] [Indexed: 01/02/2023] Open
Abstract
A spotlight has been shone on endoglin in recent years due to that fact of its potential to serve as both a reliable disease biomarker and a therapeutic target. Indeed, endoglin has now been assigned many roles in both physiological and pathological processes. From a molecular point of view, endoglin mainly acts as a co-receptor in the canonical TGFβ pathway, but also it may be shed and released from the membrane, giving rise to the soluble form, which also plays important roles in cell signaling. In cancer, in particular, endoglin may contribute to either an oncogenic or a non-oncogenic phenotype depending on the cell context. The fact that endoglin is expressed by neoplastic and non-neoplastic cells within the tumor microenvironment suggests new possibilities for targeted therapies. Here, we aimed to review and discuss the many roles played by endoglin in different tumor types, as well as the strong evidence provided by pre-clinical and clinical studies that supports the therapeutic targeting of endoglin as a novel clinical strategy.
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YAP and endothelin-1 signaling: an emerging alliance in cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:27. [PMID: 33422090 PMCID: PMC7797087 DOI: 10.1186/s13046-021-01827-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 01/03/2021] [Indexed: 12/14/2022]
Abstract
The rational making the G protein-coupled receptors (GPCR) the centerpiece of targeted therapies is fueled by the awareness that GPCR-initiated signaling acts as pivotal driver of the early stages of progression in a broad landscape of human malignancies. The endothelin-1 (ET-1) receptors (ET-1R), known as ETA receptor (ETAR) and ETB receptor (ETBR) that belong to the GPCR superfamily, affect both cancer initiation and progression in a variety of cancer types. By the cross-talking with multiple signaling pathways mainly through the scaffold protein β-arrestin1 (β-arr1), ET-1R axis cooperates with an array of molecular determinants, including transcription factors and co-factors, strongly affecting tumor cell fate and behavior. In this scenario, recent findings shed light on the interplay between ET-1 and the Hippo pathway. In ETAR highly expressing tumors ET-1 axis induces the de-phosphorylation and nuclear accumulation of the Hippo pathway downstream effectors, the paralogous transcriptional cofactors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Recent evidence have discovered that ET-1R/β-arr1 axis instigates a transcriptional interplay involving YAP and mutant p53 proteins, which share a common gene signature and cooperate in a oncogenic signaling network. Mechanistically, YAP and mutp53 are enrolled in nuclear complexes that turn on a highly selective YAP/mutp53-dependent transcriptional response. Notably, ET-1R blockade by the FDA approved dual ET-1 receptor antagonist macitentan interferes with ET-1R/YAP/mutp53 signaling interplay, through the simultaneous suppression of YAP and mutp53 functions, hampering metastasis and therapy resistance. Based on these evidences, we aim to review the recent findings linking the GPCR signaling, as for ET-1R, to YAP/TAZ signaling, underlining the clinical relevance of the blockade of such signaling network in the tumor and microenvironmental contexts. In particular, we debate the clinical implications regarding the use of dual ET-1R antagonists to blunt gain of function activity of mutant p53 proteins and thereby considering them as a potential therapeutic option for mutant p53 cancers. The identification of ET-1R/β-arr1-intertwined and bi-directional signaling pathways as targetable vulnerabilities, may open new therapeutic approaches able to disable the ET-1R-orchestrated YAP/mutp53 signaling network in both tumor and stromal cells and concurrently sensitizes to high-efficacy combined therapeutics.
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Alcendor DJ. Dysregulation of Endothelin-1: Implications for Health Disparities in Alzheimer's Disease. J Pers Med 2020; 10:E199. [PMID: 33126567 PMCID: PMC7712547 DOI: 10.3390/jpm10040199] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/24/2020] [Accepted: 10/26/2020] [Indexed: 02/07/2023] Open
Abstract
Alzheimer's disease (AD) and related dementias disproportionately impact racial and ethnic minorities. The racial and ethnic disparities in AD could be explained by differences in cerebral vascular disease pathology. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide that regulates smooth muscle, endothelial cell, and pericyte contractions that may result in cerebral vascular constriction, leading to cerebral hypoperfusion; over time, ET-1 may result in neuronal injury contributing to the pathology of AD. Upregulation of the ET-1 system has been observed in African Americans when compared with non-Hispanic Whites. The role of the ET-1 system as a driver of ethnic disparities in AD requires further investigation. Targeting of the ET-1 system as a therapeutic intervention that could impact AD progression also needs further study. Dysregulation of ET-1 in Hispanic/Latino populations largely have been unexplored. Genetics linking ET-1 dysregulation and racial disparities in AD also needs further investigation. In this review, I examine how AD effects underserved minority populations and how dysregulation of the ET-1 system specifically predisposes ethnic minorities to AD. In addition, I examine the molecular interactions of the ET-1 system and amyloid beta, the role the ET-1 system in neurodegeneration, potential therapeutics for ET-1 dysregulation, and the impact on AD progression.
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Affiliation(s)
- Donald J Alcendor
- Center for AIDS Health Disparities Research, Department of Microbiology, Immunology and Physiology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA
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Kong H, He J, Guo S, Song Q, Xiang D, Tao R, Yu H, Chen G, Huang Z, Ning Q, Huang J. Endothelin receptors promote schistosomiasis-induced hepatic fibrosis via splenic B cells. PLoS Pathog 2020; 16:e1008947. [PMID: 33075079 PMCID: PMC7595619 DOI: 10.1371/journal.ppat.1008947] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 10/29/2020] [Accepted: 08/31/2020] [Indexed: 12/17/2022] Open
Abstract
Endothelin receptors (ETRs) are activated by vasoactive peptide endothelins and involved in the pathogenesis of hepatic fibrosis. However, less is known about the role of ETRs in Schistosoma (S.) japonicum-induced hepatic fibrosis. Here, we show that the expression of ETRs is markedly enhanced in the liver and spleen tissues of patients with schistosome-induced fibrosis, as well as in murine models. Additional analyses have indicated that the expression levels of ETRs in schistosomiasis patients are highly correlated with the portal vein and spleen thickness diameter, both of which represent the severity of fibrosis. Splenomegaly is a characteristic symptom of schistosome infection, and splenic abnormality may promote the progression of hepatic fibrosis. We further demonstrate that elevated levels of ETRs are predominantly expressed on splenic B cells in spleen tissues during infection. Importantly, using a well-studied model of human schistosomiasis, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells characterized by interleukin-10 (IL-10) secretion and regulatory T (Treg) cell-inducing capacity. Our study provides insights into the mechanisms by which ETRs regulate schistosomiasis hepatic fibrosis and highlights the potential of endothelin receptor antagonist as a therapeutic intervention for fibrotic diseases. Schistosomiasis is a serious but neglected tropical infectious disease. which can lead to hepatic fibrosis and death. To date, there are still no approved antifibrotic therapies. Hepatic fibrosis results in portal hypertension and variceal bleeding, and it is the primary cause of mortality from schistosomiasis. Splenomegaly and hypersplenism can manifest following the development of portal hypertension. Accumulating evidence suggests that the spleen plays a critical role in the development of hepatic fibrosis. In this study, using Schistosoma (S.) japonicum in both humans and mice, we show that progressive hepatic schistosomiasis caused elevation of endothelin receptors (ETRs) both in liver and spleen tissues, and the endothelin receptor-producing cells are mainly located in splenic B cells. More importantly, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells during infection. Thus, our study highlights the potential of endothelin receptor antagonist as a therapeutic intervention for schistosomiasis and other fibrotic diseases.
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Affiliation(s)
- Hongyan Kong
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinan He
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shusen Guo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiqin Song
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dandan Xiang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ran Tao
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haijing Yu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guang Chen
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiyong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaquan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- * E-mail:
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Brothers RM, Stephens BY, Akins JD, Fadel PJ. Influence of sex on heightened vasoconstrictor mechanisms in the non-Hispanic black population. FASEB J 2020; 34:14073-14082. [PMID: 32949436 DOI: 10.1096/fj.202001405r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 08/20/2020] [Accepted: 08/27/2020] [Indexed: 11/11/2022]
Abstract
Cardiovascular disease (CVD) affects individuals of all races and ethnicities; however, its prevalence is highest in non-Hispanic black individuals (BL) relative to other populations. While previous research has provided valuable insight into elevated CVD risk in the BL population, this work has been almost exclusively conducted in men. This is alarming given that BL women suffer from CVD at an equivalent rate to BL men and each has a greater prevalence when compared to all other ethnicities, regardless of sex. The importance of investigating sex differences in mechanisms of cardiovascular function is highlighted by the National Institute of Health requiring sex to be considered as a biological variable in research studies to better our "understanding of key sex influences on health processes and outcomes." The mechanism(s) responsible for the elevated CVD risk in BL women remains unclear and is likely multifactorial. Limited studies in BL women suggest that, while impaired vasodilator capacity is involved, heightened vasoconstrictor tone and/or responsiveness may also contribute. Within this mini-review, we will discuss potential mechanisms of elevated rates of hypertension and other CVDs in BL individuals with a particular focus on young, otherwise healthy, college-aged women. To stimulate academic thought and future research, we will also discuss potential mechanisms for impaired vascular function in BL women, as well as possible divergent mechanisms between BL men and women based on either preliminary data or plausible speculation extending from findings in the existing literature. Last, we will conclude with potential future research directions aimed at better understanding the elevated risk for hypertension and CVD in BL women.
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Affiliation(s)
| | | | - John D Akins
- Department of Kinesiology, University of Texas, Arlington, TX, USA
| | - Paul J Fadel
- Department of Kinesiology, University of Texas, Arlington, TX, USA
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Czopek A, Moorhouse R, Guyonnet L, Farrah T, Lenoir O, Owen E, van Bragt J, Costello HM, Menolascina F, Baudrie V, Webb DJ, Kluth DC, Bailey MA, Tharaux PL, Dhaun N. A novel role for myeloid endothelin-B receptors in hypertension. Eur Heart J 2020; 40:768-784. [PMID: 30657897 PMCID: PMC6396028 DOI: 10.1093/eurheartj/ehy881] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 09/04/2018] [Accepted: 12/10/2018] [Indexed: 12/11/2022] Open
Abstract
AIMS Hypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype. METHODS AND RESULTS In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB-/-), we explored the effects of modifying Mφ number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB-/- mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies. CONCLUSION Mφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.
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Affiliation(s)
- Alicja Czopek
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Rebecca Moorhouse
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Léa Guyonnet
- Paris Cardiovascular Research Centre - PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Tariq Farrah
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Olivia Lenoir
- Paris Cardiovascular Research Centre - PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Elizabeth Owen
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Job van Bragt
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Hannah M Costello
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Filippo Menolascina
- School of Engineering & SynthSys, Institute for Bioengineering, Centre for Synthetic and Systems Biology, University of Edinburgh, Edinburgh, UK.,MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Véronique Baudrie
- Paris Cardiovascular Research Centre - PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - David J Webb
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - David C Kluth
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Matthew A Bailey
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Pierre-Louis Tharaux
- Paris Cardiovascular Research Centre - PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.,Paris Descartes University, Sorbonne Paris Cité, Paris, France
| | - Neeraj Dhaun
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK.,Paris Cardiovascular Research Centre - PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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50
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Maki H, Hara T, Tsuji M, Saito A, Minatsuki S, Inaba T, Amiya E, Hosoya Y, Hatano M, Morita H, Yao A, Kinugawa K, Komuro I. The Clinical Efficacy of Endothelin Receptor Antagonists in Patients with Pulmonary Arterial Hypertension. Int Heart J 2020; 61:799-805. [PMID: 32728000 DOI: 10.1536/ihj.20-173] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.
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Affiliation(s)
- Hisataka Maki
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
| | - Toru Hara
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
| | - Masaki Tsuji
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
| | - Akihito Saito
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
| | - Shun Minatsuki
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
| | - Toshiro Inaba
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
| | - Eisuke Amiya
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.,Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo
| | - Yumiko Hosoya
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.,Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo
| | - Masaru Hatano
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.,Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo
| | - Hiroyuki Morita
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
| | - Atsushi Yao
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.,Division for Health Service Promotion, The University of Tokyo
| | | | - Issei Komuro
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
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