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Lockwood F, Lachaux M, Harouki N, Soulié M, Nicol L, Renet S, Dumesnil A, Vercauteren M, Bellien J, Iglarz M, Richard V, Mulder P. Dual ET A-ET B receptor antagonism improves metabolic syndrome-induced heart failure with preserved ejection fraction. Fundam Clin Pharmacol 2025; 39:e70006. [PMID: 40203840 PMCID: PMC11981691 DOI: 10.1111/fcp.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 02/19/2025] [Accepted: 03/05/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND Metabolic syndrome (MetS) is a multifaceted disease associated with heart failure (HF), which affects the vascular system. The endothelin (ET) system is a key player in MetS and HF; therefore, targets for ET receptors are of therapeutic interest. OBJECTIVES This study sought to evaluate the effects of macitentan, a dual endothelin receptor antagonist (ERA), in a rat model of MetS-induced heart failure with preserved ejection fraction (HFpEF). METHODS We assessed in 12-week-old Zucker fa/fa rats the effects of macitentan (10 mg/kg/day as a food additive for short-term/7- or long-term/90-day treatment) on right ventricular (RV) and left ventricular (LV) function/remodelling (MRI), RV and LV haemodynamics (catheterization) and RV and LV coronary function (myograph). RESULTS After 7- and 90-days, untreated Zucker fa/fa rats presented isolated LV diastolic dysfunction (illustrated by elevated LV end-diastolic pressure [EDP] and LV end-diastolic pressure-volume relationship [EDPVR] without changes in LV EDPVR). This was associated with increased collagen deposition and impaired endothelium-dependent coronary artery relaxation. Macitentan 7- and 90-day treatment significantly decreased blood pressure and prevented LV, RV and coronary dysfunctions and long-term treatment reduced LV collagen density. Moreover, 7- and 90-day macitentan treatment significantly reduced cardiac inflammation and reactive oxygen species (ROS) production. CONCLUSIONS Dual ERA macitentan improved both LV and RV diastolic dysfunction. This was associated with improved coronary vasodilation, diminished cardiac oxidative stress and improved blood composition. These results suggest that antagonizing the ET system with macitentan is a promising approach to treat HFpEF and its complications.
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Affiliation(s)
- Francesca Lockwood
- Univ Rouen Normandie, INSERM U1096, EnVIRouenFrance
- Institute for Clinical Medicine, Medical FacultyUniversity of OsloOsloNorway
| | | | | | | | - Lionel Nicol
- Univ Rouen Normandie, INSERM U1096, EnVIRouenFrance
| | | | | | | | | | - Marc Iglarz
- Idorsia Pharmaceuticals Ltd.AllschwilSwitzerland
| | | | - Paul Mulder
- Univ Rouen Normandie, INSERM U1096, EnVIRouenFrance
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2
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Adao DMT, Ching C, Fish JE, Simmons CA, Billia F. Endothelial cell-cardiomyocyte cross-talk: understanding bidirectional paracrine signaling in cardiovascular homeostasis and disease. Clin Sci (Lond) 2024; 138:1395-1419. [PMID: 39492693 DOI: 10.1042/cs20241084] [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: 06/09/2024] [Revised: 10/10/2024] [Accepted: 10/21/2024] [Indexed: 11/05/2024]
Abstract
To maintain homeostasis in the heart, endothelial cells and cardiomyocytes engage in dynamic cross-talk through paracrine signals that regulate both cardiac development and function. Here, we review the paracrine signals that endothelial cells release to regulate cardiomyocyte growth, hypertrophy and contractility, and the factors that cardiomyocytes release to influence angiogenesis and vascular tone. Dysregulated communication between these cell types can drive pathophysiology of disease, as seen in ischemia-reperfusion injury, diabetes, maladaptive hypertrophy, and chemotherapy-induced cardiotoxicity. Investingating the role of cross-talk is critical in developing an understanding of tissue homeostasis, regeneration, and disease pathogenesis, with the potential to identify novel targets for diagnostic and therapeutic purposes.
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Affiliation(s)
- Doris M T Adao
- Institute of Biomedical Engineering, University of Toronto, 164 College St., Toronto, Ontario, Canada, M5S 3G9
- Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, 661 University Ave., Toronto, Ontario, Canada, M5G 1M1
- Toronto General Hospital Research Institute, University Health Network, 100 College St., Toronto, Ontario Canada, M5G 1L7
| | - Crizza Ching
- Toronto General Hospital Research Institute, University Health Network, 100 College St., Toronto, Ontario Canada, M5G 1L7
- Institute of Medical Science, University of Toronto, 1 King's College Cir., Toronto, Ontario, Canada, M5G 1A8
| | - Jason E Fish
- Toronto General Hospital Research Institute, University Health Network, 100 College St., Toronto, Ontario Canada, M5G 1L7
- Institute of Medical Science, University of Toronto, 1 King's College Cir., Toronto, Ontario, Canada, M5G 1A8
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Cir., Toronto, Ontario, Canada, M5G 1A8
- Peter Munk Cardiac Centre, University Health Network, 585 University Ave., Toronto, Ontario, Canada, M5G 2N2
| | - Craig A Simmons
- Institute of Biomedical Engineering, University of Toronto, 164 College St., Toronto, Ontario, Canada, M5S 3G9
- Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, 661 University Ave., Toronto, Ontario, Canada, M5G 1M1
- Department of Mechanical and Industrial Engineering, University of Toronto, 5 King's College Rd., Toronto, Ontario, Canada, M5S 3G8
| | - Filio Billia
- Toronto General Hospital Research Institute, University Health Network, 100 College St., Toronto, Ontario Canada, M5G 1L7
- Institute of Medical Science, University of Toronto, 1 King's College Cir., Toronto, Ontario, Canada, M5G 1A8
- Peter Munk Cardiac Centre, University Health Network, 585 University Ave., Toronto, Ontario, Canada, M5G 2N2
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Varzideh F, Jankauskas SS, Jain U, Soderquist L, Densu Agyapong E, Kansakar U, Santulli G. The dual endothelin-1 antagonist aprocitentan alleviates mitochondrial oxidative stress in human cardiac fibroblasts. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2024; 10:566-568. [PMID: 38977898 PMCID: PMC11450266 DOI: 10.1093/ehjcvp/pvae050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 05/29/2024] [Accepted: 07/05/2024] [Indexed: 07/10/2024]
Affiliation(s)
- Fahimeh Varzideh
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein-Sinai Diabetes Research Center, Einstein Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, New York City, NY, USA
| | - Stanislovas S Jankauskas
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein-Sinai Diabetes Research Center, Einstein Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, New York City, NY, USA
| | - Urja Jain
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein-Sinai Diabetes Research Center, Einstein Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, New York City, NY, USA
| | - Lauren Soderquist
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein-Sinai Diabetes Research Center, Einstein Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, New York City, NY, USA
| | - Esther Densu Agyapong
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein-Sinai Diabetes Research Center, Einstein Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, New York City, NY, USA
| | - Urna Kansakar
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein-Sinai Diabetes Research Center, Einstein Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, New York City, NY, USA
| | - Gaetano Santulli
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein-Sinai Diabetes Research Center, Einstein Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, New York City, NY, USA
- Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism - FIDAM, Einstein Institute for Neuroimmunology and Inflammation, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, New York City, NY, USA
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Ram CVS. A New Class of Drugs Approved in the United States for Hypertension: Endothelin Antagonists. Am J Med 2024; 137:795-798. [PMID: 38750711 DOI: 10.1016/j.amjmed.2024.04.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 04/25/2024] [Indexed: 06/10/2024]
Affiliation(s)
- C Venkata S Ram
- Apollo Group of Hospitals, Hyderabad, India; University of Texas Southwestern Medical Center, Dallas.
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5
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Thai BS, Chia LY, Nguyen ATN, Qin C, Ritchie RH, Hutchinson DS, Kompa A, White PJ, May LT. Targeting G protein-coupled receptors for heart failure treatment. Br J Pharmacol 2024; 181:2270-2286. [PMID: 37095602 DOI: 10.1111/bph.16099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 04/10/2023] [Accepted: 04/13/2023] [Indexed: 04/26/2023] Open
Abstract
Heart failure remains a leading cause of morbidity and mortality worldwide. Current treatment for patients with heart failure include drugs targeting G protein-coupled receptors such as β-adrenoceptor antagonists (β-blockers) and angiotensin II type 1 receptor antagonists (or angiotensin II receptor blockers). However, many patients progress to advanced heart failure with persistent symptoms, despite treatment with available therapeutics that have been shown to reduce mortality and mortality. GPCR targets currently being explored for the development of novel heart failure therapeutics include adenosine receptor, formyl peptide receptor, relaxin/insulin-like family peptide receptor, vasopressin receptor, endothelin receptor and the glucagon-like peptide 1 receptor. Many GPCR drug candidates are limited by insufficient efficacy and/or dose-limiting unwanted effects. Understanding the current challenges hindering successful clinical translation and the potential to overcome existing limitations will facilitate the future development of novel heart failure therapeutics. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.
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Affiliation(s)
- Bui San Thai
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Ling Yeong Chia
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Anh T N Nguyen
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Chengxue Qin
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Rebecca H Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Dana S Hutchinson
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Andrew Kompa
- Department Medicine and Radiology, University of Melbourne, St Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Paul J White
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Lauren T May
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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Stasinopoulou M, Kostomitsopoulos N, Kadoglou NPE. The Anti-Atherosclerotic Effects of Endothelin Receptor Antagonist, Bosentan, in Combination with Atorvastatin-An Experimental Study. Int J Mol Sci 2024; 25:6614. [PMID: 38928320 PMCID: PMC11203450 DOI: 10.3390/ijms25126614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG (p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG (p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG (p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE-/- mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.
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Affiliation(s)
- Marianna Stasinopoulou
- Center of Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation, Academy of Athens, 115 27 Athens, Greece; (M.S.); (N.K.)
| | - Nikolaos Kostomitsopoulos
- Center of Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation, Academy of Athens, 115 27 Athens, Greece; (M.S.); (N.K.)
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Lin R, Junttila J, Piuhola J, Lepojärvi ES, Magga J, Kiviniemi AM, Perkiömäki J, Huikuri H, Ukkola O, Tulppo M, Kerkelä R. Endothelin-1 is associated with mortality that can be attenuated with high intensity statin therapy in patients with stable coronary artery disease. COMMUNICATIONS MEDICINE 2023; 3:87. [PMID: 37349571 PMCID: PMC10287654 DOI: 10.1038/s43856-023-00322-9] [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: 11/14/2022] [Accepted: 06/12/2023] [Indexed: 06/24/2023] Open
Abstract
BACKGROUND All coronary artery disease (CAD) patients do not benefit equally of secondary prevention. Individualized intensity of drug therapy is currently implemented in guidelines for CAD and diabetes. Novel biomarkers are needed to identify patient subgroups potentially benefitting from individual therapy. This study aimed to investigate endothelin-1 (ET-1) as a biomarker for increased risk of adverse events and to evaluate if medication could alleviate the risks in patients with high ET-1. METHODS A prospective observational cohort study ARTEMIS included 1946 patients with angiographically documented CAD. Blood samples and baseline data were collected at enrollment and the patients were followed for 11 years. Multivariable Cox regression was used to assess the association between circulating ET-1 level and all-cause mortality, cardiovascular (CV) death, non-CV death and sudden cardiac death (SCD). RESULTS Here we show an association of circulating ET-1 level with higher risk for all-cause mortality (HR: 2.06; 95% CI 1.5-2.83), CV death, non-CV death and SCD in patients with CAD. Importantly, high intensity statin therapy reduces the risk for all-cause mortality (adjusted HR: 0.05; 95% CI 0.01-0.38) and CV death (adjusted HR: 0.06; 95% CI 0.01-0.44) in patients with high ET-1, but not in patients with low ET-1. High intensity statin therapy does not associate with reduction of risk for non-CV death or SCD. CONCLUSIONS Our data suggests a prognostic value for high circulating ET-1 in patients with stable CAD. High intensity statin therapy associates with reduction of risk for all-cause mortality and CV death in CAD patients with high ET-1.
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Affiliation(s)
- Ruizhu Lin
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
| | - Juhani Junttila
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
- Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
- Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Jarkko Piuhola
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
| | - E Samuli Lepojärvi
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
| | - Johanna Magga
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
- Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Antti M Kiviniemi
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
| | - Juha Perkiömäki
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
| | - Heikki Huikuri
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
| | - Olavi Ukkola
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
| | - Mikko Tulppo
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
| | - Risto Kerkelä
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland.
- Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
- Biocenter Oulu, University of Oulu, Oulu, Finland.
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8
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Duangrat R, Parichatikanond W, Likitnukul S, Mangmool S. Endothelin-1 Induces Cell Proliferation and Myofibroblast Differentiation through the ET AR/G αq/ERK Signaling Pathway in Human Cardiac Fibroblasts. Int J Mol Sci 2023; 24:ijms24054475. [PMID: 36901906 PMCID: PMC10002923 DOI: 10.3390/ijms24054475] [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: 01/16/2023] [Revised: 02/10/2023] [Accepted: 02/21/2023] [Indexed: 03/12/2023] Open
Abstract
Endothelin-1 (ET-1) has been implicated in the pathogenesis of cardiac fibrosis. Stimulation of endothelin receptors (ETR) with ET-1 leads to fibroblast activation and myofibroblast differentiation, which is mainly characterized by an overexpression of α-smooth muscle actin (α-SMA) and collagens. Although ET-1 is a potent profibrotic mediator, the signal transductions and subtype specificity of ETR contributing to cell proliferation, as well as α-SMA and collagen I synthesis in human cardiac fibroblasts are not well clarified. This study aimed to evaluate the subtype specificity and signal transduction of ETR on fibroblast activation and myofibroblast differentiation. Treatment with ET-1 induced fibroblast proliferation, and synthesis of myofibroblast markers, α-SMA, and collagen I through the ETAR subtype. Inhibition of Gαq protein, not Gαi or Gβγ, inhibited these effects of ET-1, indicating the essential role of Gαq protein-mediated ETAR signaling. In addition, ERK1/2 was required for ETAR/Gαq axis-induced proliferative capacity and overexpression of these myofibroblast markers. Antagonism of ETR with ETR antagonists (ERAs), ambrisentan and bosentan, inhibited ET-1-induced cell proliferation and synthesis of α-SMA and collagen I. Furthermore, ambrisentan and bosentan promoted the reversal of myofibroblasts after day 3 of treatment, with loss of proliferative ability and a reduction in α-SMA synthesis, confirming the restorative effects of ERAs. This novel work reports on the ETAR/Gαq/ERK signaling pathway for ET-1 actions and blockade of ETR signaling with ERAs, representing a promising therapeutic strategy for prevention and restoration of ET-1-induced cardiac fibrosis.
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Affiliation(s)
- Ratchanee Duangrat
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
- Molecular Medicine Graduate Program, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Warisara Parichatikanond
- Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
- Centre of Biopharmaceutical Science for Healthy Ageing (BSHA), Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Sutharinee Likitnukul
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Supachoke Mangmool
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
- Correspondence:
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Sikiric P, Udovicic M, Barisic I, Balenovic D, Zivanovic Posilovic G, Strinic D, Uzun S, Sikiric S, Krezic I, Zizek H, Yago H, Gojkovic S, Smoday IM, Kalogjera L, Vranes H, Sola M, Strbe S, Koprivanac A, Premuzic Mestrovic I, Mestrovic T, Pavic P, Skrtic A, Blagaic AB, Lovric Bencic M, Seiwerth S. Stable Gastric Pentadecapeptide BPC 157 as Useful Cytoprotective Peptide Therapy in the Heart Disturbances, Myocardial Infarction, Heart Failure, Pulmonary Hypertension, Arrhythmias, and Thrombosis Presentation. Biomedicines 2022; 10:2696. [PMID: 36359218 PMCID: PMC9687817 DOI: 10.3390/biomedicines10112696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/08/2022] [Accepted: 10/15/2022] [Indexed: 11/30/2022] Open
Abstract
In heart disturbances, stable gastric pentadecapeptide BPC 157 especial therapy effects combine the therapy of myocardial infarction, heart failure, pulmonary hypertension arrhythmias, and thrombosis prevention and reversal. The shared therapy effect occurred as part of its even larger cytoprotection (cardioprotection) therapy effect (direct epithelial cell protection; direct endothelium cell protection) that BPC 157 exerts as a novel cytoprotection mediator, which is native and stable in human gastric juice, as well as easily applicable. Accordingly, there is interaction with many molecular pathways, combining maintained endothelium function and maintained thrombocytes function, which counteracted thrombocytopenia in rats that underwent major vessel occlusion and deep vein thrombosis and counteracted thrombosis in all vascular studies; the coagulation pathways were not affected. These appeared as having modulatory effects on NO-system (NO-release, NOS-inhibition, NO-over-stimulation all affected), controlling vasomotor tone and the activation of the Src-Caveolin-1-eNOS pathway and modulatory effects on the prostaglandins system (BPC 157 counteracted NSAIDs toxicity, counteracted bleeding, thrombocytopenia, and in particular, leaky gut syndrome). As an essential novelty noted in the vascular studies, there was the activation of the collateral pathways. This might be the upgrading of the minor vessel to take over the function of the disabled major vessel, competing with and counteracting the Virchow triad circumstances devastatingly present, making possible the recruitment of collateral blood vessels, compensating vessel occlusion and reestablishing the blood flow or bypassing the occluded or ruptured vessel. As a part of the counteraction of the severe vessel and multiorgan failure syndrome, counteracted were the brain, lung, liver, kidney, gastrointestinal lesions, and in particular, the counteraction of the heart arrhythmias and infarction.
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Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Mario Udovicic
- Department of Internal Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Diana Balenovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | | | - Dean Strinic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sandra Uzun
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Haidi Yago
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Luka Kalogjera
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Marija Sola
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Antun Koprivanac
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | | | - Tomislav Mestrovic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Predrag Pavic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Martina Lovric Bencic
- Department of Internal Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Targeting Myocardial Fibrosis—A Magic Pill in Cardiovascular Medicine? Pharmaceutics 2022; 14:pharmaceutics14081599. [PMID: 36015225 PMCID: PMC9414721 DOI: 10.3390/pharmaceutics14081599] [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: 06/21/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 11/16/2022] Open
Abstract
Fibrosis, characterized by an excessive accumulation of extracellular matrix, has long been seen as an adaptive process that contributes to tissue healing and regeneration. More recently, however, cardiac fibrosis has been shown to be a central element in many cardiovascular diseases (CVDs), contributing to the alteration of cardiac electrical and mechanical functions in a wide range of clinical settings. This paper aims to provide a comprehensive review of cardiac fibrosis, with a focus on the main pathophysiological pathways involved in its onset and progression, its role in various cardiovascular conditions, and on the potential of currently available and emerging therapeutic strategies to counteract the development and/or progression of fibrosis in CVDs. We also emphasize a number of questions that remain to be answered, and we identify hotspots for future research.
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Abstract
The development of pulmonary hypertension (PH) is common and has adverse prognostic implications in patients with heart failure due to left heart disease (LHD), and thus far, there are no known treatments specifically for PH-LHD, also known as group 2 PH. Diagnostic thresholds for PH-LHD, and clinical classification of PH-LHD phenotypes, continue to evolve and, therefore, present a challenge for basic and translational scientists actively investigating PH-LHD in the preclinical setting. Furthermore, the pathobiology of PH-LHD is not well understood, although pulmonary vascular remodeling is thought to result from (1) increased wall stress due to increased left atrial pressures; (2) hemodynamic congestion-induced decreased shear stress in the pulmonary vascular bed; (3) comorbidity-induced endothelial dysfunction with direct injury to the pulmonary microvasculature; and (4) superimposed pulmonary arterial hypertension risk factors. To ultimately be able to modify disease, either by prevention or treatment, a better understanding of the various drivers of PH-LHD, including endothelial dysfunction, abnormalities in vascular tone, platelet aggregation, inflammation, adipocytokines, and systemic complications (including splanchnic congestion and lymphatic dysfunction) must be further investigated. Here, we review the diagnostic criteria and various hemodynamic phenotypes of PH-LHD, the potential biological mechanisms underlying this disorder, and pressing questions yet to be answered about the pathobiology of PH-LHD.
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Affiliation(s)
- Jessica H Huston
- Division of Cardiology, Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA (J.H.H.)
| | - Sanjiv J Shah
- Division of Cardiology, Department of Medicine, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.)
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12
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Hula N, Vu J, Quon A, Kirschenman R, Spaans F, Liu R, Cooke CLM, Davidge ST. Sex-Specific Effects of Prenatal Hypoxia on the Cardiac Endothelin System in Adult Offspring. Am J Physiol Heart Circ Physiol 2022; 322:H442-H450. [PMID: 35119336 DOI: 10.1152/ajpheart.00636.2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Fetal hypoxia, a major consequence of complicated pregnancies, impairs offspring cardiac tolerance to ischemia/reperfusion (I/R) insult, however, the mechanisms remain unknown. Endothelin-1 (ET-1) signaling through the endothelin A receptors (ETA) is associated with cardiac dysfunction. We hypothesized that prenatal hypoxia exacerbates cardiac susceptibility to I/R via increased ET-1 and ETA levels, while ETA inhibition ameliorates this. Pregnant Sprague-Dawley rats were exposed to normoxia (21% O2) or hypoxia (11% O2) on gestational days 15-21. Offspring were aged to 4 months, and hearts were aerobically perfused or subjected to ex vivo I/R, with or without pre-infusion with an ETA antagonist (ABT-627). ET-1 levels were assessed with ELISA in aerobically perfused and post-I/R left ventricles (LV). ETA and ETB levels were assessed by Western blotting in non-perfused LV. As hypothesized, ABT-627 infusion tended to improve post-I/R recovery in hypoxic females (p=0.0528), however, surprisingly, ABT-627 prevented post-I/R recovery only in the hypoxic males (p<0.001). ET-1 levels were increased in post-I/R LV in both sexes regardless of the prenatal exposure (p<0.01). ETA expression was similar among all groups, while ETB (isoform C) levels were decreased in prenatally hypoxic females (p<0.05). In prenatally hypoxic males, ETA signaling may be essential for tolerance to I/R, while in prenatally hypoxic females, ETA may contribute to cardiac dysfunction. Our data illustrate that understanding the prenatal history has critical implications for treatment strategies in adult chronic diseases.
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Affiliation(s)
- Nataliia Hula
- Department of Physiology, University of Alberta, Edmonton, Canada.,Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
| | - Jennie Vu
- Department of Physiology, University of Alberta, Edmonton, Canada
| | - Anita Quon
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
| | - Raven Kirschenman
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
| | - Floor Spaans
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
| | - Ricky Liu
- Department of Physiology, University of Alberta, Edmonton, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
| | - Christy-Lynn M Cooke
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
| | - Sandra T Davidge
- Department of Physiology, University of Alberta, Edmonton, Canada.,Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
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13
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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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14
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Lteif C, Ataya A, Duarte JD. Therapeutic Challenges and Emerging Treatment Targets for Pulmonary Hypertension in Left Heart Disease. J Am Heart Assoc 2021; 10:e020633. [PMID: 34032129 PMCID: PMC8483544 DOI: 10.1161/jaha.120.020633] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pulmonary hypertension (PH) attributable to left heart disease (LHD) is believed to be the most common form of PH and is strongly associated with increased mortality and morbidity in this patient population. Specific therapies for PH‐LHD have not yet been identified and the use of pulmonary artery hypertension‐targeted therapies in PH‐LHD are not recommended. Endothelin receptor antagonists, phosphodiesterase‐5 inhibitors, guanylate cyclase stimulators, and prostacyclins have all been studied in PH‐LHD with conflicting results. Understanding the mechanisms underlying PH‐LHD could potentially provide novel therapeutic targets. Fibrosis, oxidative stress, and metabolic syndrome have been proposed as pathophysiological components of PH‐LHD. Genetic associations have also been identified, offering additional mechanisms with biological plausibility. This review summarizes the evidence and challenges for treatment of PH‐LHD and focuses on underlying mechanisms on the horizon that could develop into potential therapeutic targets for this disease.
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Affiliation(s)
- Christelle Lteif
- Department of Pharmacotherapy and Translational Research Center for Pharmacogenomics and Precision Medicine University of Florida College of Pharmacy Gainesville FL
| | - Ali Ataya
- Division of Pulmonary, Critical Care & Sleep Medicine University of Florida College of Medicine Gainesville FL
| | - Julio D Duarte
- Department of Pharmacotherapy and Translational Research Center for Pharmacogenomics and Precision Medicine University of Florida College of Pharmacy Gainesville FL
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15
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Mahajan R, Lau DH, Brooks AG, Shipp NJ, Wood JPM, Manavis J, Samuel CS, Patel KP, Finnie JW, Alasady M, Kalman JM, Sanders P. Atrial Fibrillation and Obesity: Reverse Remodeling of Atrial Substrate With Weight Reduction. JACC Clin Electrophysiol 2021; 7:630-641. [PMID: 33640353 DOI: 10.1016/j.jacep.2020.11.015] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 11/18/2022]
Abstract
OBJECTIVES This study sought to evaluate the effect of weight loss on the atrial substrate for atrial fibrillation (AF). BACKGROUND Whether weight loss can reverse the atrial substrate of obesity is not known. METHODS Thirty sheep had sustained obesity induced by ad libitum calorie-dense diet over 72 weeks. Animals were randomized to 3 groups: sustained obesity and 15% and 30% weight loss. The animals randomized to weight loss underwent weight reduction by reducing the quantity of hay over 32 weeks. Eight lean animals served as controls. All were subjected to the following: dual-energy x-ray absorptiometry, echocardiogram, cardiac magnetic resonance, electrophysiological study, and histological and molecular analyses (fatty infiltration, fibrosis, transforming growth factor β1, and connexin 43). RESULTS Sustained obesity was associated with increased left atrium (LA) pressure (p < 0.001), inflammation (p < 0.001), atrial transforming growth factor β1 protein (p < 0.001), endothelin-B receptor expression (p = 0.04), atrial fibrosis (p = 0.01), epicardial fat infiltration (p < 0.001), electrophysiological abnormalities, and AF burden (p = 0.04). Connexin 43 expression was decreased in the obese group (p = 0.03). In this obese ovine model, 30% weight reduction was associated with reduction in total body fat (p < 0.001), LA pressure (p = 0.007), inflammation (p < 0.001), endothelin-B receptor expression (p = 0.01), atrial fibrosis (p = 0.01), increase in atrial effective refractory period (cycle length: 400 and 300 ms; p < 0.001), improved conduction velocity (cycle length: 400 and 300 ms; p = 0.01), decreased conduction heterogeneity (p < 0.001), and decreased AF inducibility (p = 0.03). Weight loss was associated with a nonsignificant reduction in epicardial fat infiltration in posterior LA (p = 0.34). CONCLUSIONS Weight loss in an obese ovine model is associated with structural and electrophysiological reverse remodeling and a reduced propensity for AF. This provides evidence for the direct role of obesity in AF substrate and the role of weight reduction in patients with AF.
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Affiliation(s)
- Rajiv Mahajan
- Centre for Heart Rhythm Disorders, University of Adelaide, Adelaide, Australia; Department of Cardiology, Lyell McEwin Hospital, Adelaide, Australia
| | - Dennis H Lau
- Centre for Heart Rhythm Disorders, University of Adelaide, Adelaide, Australia; Department of Cardiology, Royal Adelaide Hospital, Adelaide, Australia
| | - Anthony G Brooks
- Centre for Heart Rhythm Disorders, University of Adelaide, Adelaide, Australia
| | - Nicholas J Shipp
- Centre for Heart Rhythm Disorders, University of Adelaide, Adelaide, Australia
| | - John P M Wood
- Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide; SA Pathology, Adelaide, Australia
| | - Jim Manavis
- Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide; SA Pathology, Adelaide, Australia
| | - Chrishan S Samuel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Melbourne, Australia
| | - Krupesh P Patel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Melbourne, Australia
| | - John W Finnie
- Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide; SA Pathology, Adelaide, Australia
| | - Muayad Alasady
- Centre for Heart Rhythm Disorders, University of Adelaide, Adelaide, Australia; Department of Cardiology, Royal Adelaide Hospital, Adelaide, Australia
| | - Jonathan M Kalman
- Department of Cardiology, Royal Melbourne Hospital and University of Melbourne, Melbourne, Australia
| | - Prashanthan Sanders
- Centre for Heart Rhythm Disorders, University of Adelaide, Adelaide, Australia; Department of Cardiology, Royal Adelaide Hospital, Adelaide, Australia.
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16
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Prokudina ES, Kurbatov BK, Zavadovsky KV, Vrublevsky AV, Naryzhnaya NV, Lishmanov YB, Maslov LN, Oeltgen PR. Takotsubo Syndrome: Clinical Manifestations, Etiology and Pathogenesis. Curr Cardiol Rev 2021; 17:188-203. [PMID: 31995013 PMCID: PMC8226199 DOI: 10.2174/1573403x16666200129114330] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 12/02/2019] [Accepted: 12/12/2019] [Indexed: 12/15/2022] Open
Abstract
The purpose of the review is the analysis of clinical and experimental data on the etiology and pathogenesis of takotsubo syndrome (TS). TS is characterized by contractile dysfunction, which usually affects the apical region of the heart without obstruction of coronary artery, moderate increase in myocardial necrosis markers, prolonged QTc interval (in 50% of patients), sometimes elevation of ST segment (in 19% of patients), increase N-Terminal Pro-B-Type Natriuretic Peptide level, microvascular dysfunction, sometimes spasm of the epicardial coronary arteries (in 10% of patients), myocardial edema, and life-threatening ventricular arrhythmias (in 11% of patients). Stress cardiomyopathy is a rare disease, it is observed in 0.6 - 2.5% of patients with acute coronary syndrome. The occurrence of takotsubo syndrome is 9 times higher in women, who are aged 60-70 years old, than in men. The hospital mortality among patients with TS corresponds to 3.5% - 12%. Physical or emotional stress do not precede disease in all patients with TS. Most of patients with TS have neurological or mental illnesses. The level of catecholamines is increased in patients with TS, therefore, the occurrence of TS is associated with excessive activation of the adrenergic system. The negative inotropic effect of catecholamines is associated with the activation of β2 adrenergic receptors. An important role of the adrenergic system in the pathogenesis of TS is confirmed by studies which were performed using 125I-metaiodobenzylguanidine (125I -MIBG). TS causes edema and inflammation of the myocardium. The inflammatory response in TS is systemic. TS causes impaired coronary microcirculation and reduces coronary reserve. There is a reason to believe that an increase in blood viscosity may play an important role in the pathogenesis of microcirculatory dysfunction in patients with TS. Epicardial coronary artery spasm is not obligatory for the occurrence of TS. Cortisol, endothelin-1 and microRNAs are challengers for the role of TS triggers. A decrease in estrogen levels is a factor contributing to the onset of TS. The central nervous system appears to play an important role in the pathogenesis of TS.
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Affiliation(s)
- Ekaterina S Prokudina
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center of the RAS, Tomsk, Russian Federation
| | - Boris K Kurbatov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center of the RAS, Tomsk, Russian Federation
| | - Konstantin V Zavadovsky
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center of the RAS, Tomsk, Russian Federation
| | - Alexander V Vrublevsky
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center of the RAS, Tomsk, Russian Federation
| | - Natalia V Naryzhnaya
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center of the RAS, Tomsk, Russian Federation
| | - Yuri B Lishmanov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center of the RAS, Tomsk, Russian Federation
| | - Leonid N Maslov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center of the RAS, Tomsk, Russian Federation
| | - Peter R Oeltgen
- Department of Pathology, University of Kentucky College of Medicine, Lexington, KY 40506, United States
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17
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Abstract
Myocardial fibrosis, the expansion of the cardiac interstitium through deposition of extracellular matrix proteins, is a common pathophysiologic companion of many different myocardial conditions. Fibrosis may reflect activation of reparative or maladaptive processes. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. Immune cells, vascular cells and cardiomyocytes may also acquire a fibrogenic phenotype under conditions of stress, activating fibroblast populations. Fibrogenic growth factors (such as transforming growth factor-β and platelet-derived growth factors), cytokines [including tumour necrosis factor-α, interleukin (IL)-1, IL-6, IL-10, and IL-4], and neurohumoral pathways trigger fibrogenic signalling cascades through binding to surface receptors, and activation of downstream signalling cascades. In addition, matricellular macromolecules are deposited in the remodelling myocardium and regulate matrix assembly, while modulating signal transduction cascades and protease or growth factor activity. Cardiac fibroblasts can also sense mechanical stress through mechanosensitive receptors, ion channels and integrins, activating intracellular fibrogenic cascades that contribute to fibrosis in response to pressure overload. Although subpopulations of fibroblast-like cells may exert important protective actions in both reparative and interstitial/perivascular fibrosis, ultimately fibrotic changes perturb systolic and diastolic function, and may play an important role in the pathogenesis of arrhythmias. This review article discusses the molecular mechanisms involved in the pathogenesis of cardiac fibrosis in various myocardial diseases, including myocardial infarction, heart failure with reduced or preserved ejection fraction, genetic cardiomyopathies, and diabetic heart disease. Development of fibrosis-targeting therapies for patients with myocardial diseases will require not only understanding of the functional pluralism of cardiac fibroblasts and dissection of the molecular basis for fibrotic remodelling, but also appreciation of the pathophysiologic heterogeneity of fibrosis-associated myocardial disease.
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Affiliation(s)
- Nikolaos G Frangogiannis
- Department of Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY 10461, USA
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18
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Effect of high-intensity interval training on cardiac structure and function in rats with acute myocardial infarct. Biomed Pharmacother 2020; 131:110690. [PMID: 32890969 DOI: 10.1016/j.biopha.2020.110690] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/24/2020] [Accepted: 08/25/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Exercise training is beneficial for cardiac rehabilitation. Nevertheless, few study focused on the role of high-intensity interval training (HIIT) in cardiac repair. The current study aimed to elucidate the effect of HIIT on cardiac rehabilitation and the involved mechanisms after acute myocardial infarction (MI). METHODS A total of 65 male rats underwent coronary ligation or sham operation and were randomly assigned to 4 groups: sham (n = 10), sedentary (MI-Sed, n = 12), moderate-intensity continuous training (MI-MCT, n = 12) and HIIT (MI-HIIT, n = 12). One week after MI induction, adaptive training starts follow by formal training. After the experiment, cardiac functions were determined by echocardiography and hemodynamic measurements. Changes in infarct size, collagen accumulation, myofibroblasts, angiogenesis, inflammation level, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system (RAAS) activities were measured. Data were analyzed by one-way ANOVA. RESULTS After MI, cardiac structure and function were significantly deteriorated. However, post-MI HIIT for 8 weeks had significantly ameliorated left ventricular end-diastolic pressure (LVEDP), LV systolic pressure (LVSP), and maximum peak velocities of relaxation (-dP/dtmax). Moreover, it preserved cardiac functions, reduced infarct size, protected the myocardium structure, increased angiogenesis and decreased the myofibroblasts and collagen accumulation. HIIT for 4 weeks had no effect on LVEDP, -dP/dtmax, infarct size and angiogenesis. Additionally, it induced inflammation response and repressed ET-1 and RAAS activities were found in myocardium and peripheral circulation after HIIT. CONCLUSION Our results suggested that post-MI HIIT had a positive role in cardiac repair, which might be linked with the induction of inflammation and inhibition of ET-1 and RAAS activities.
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19
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Borovac JA, D'Amario D, Bozic J, Glavas D. Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers. World J Cardiol 2020; 12:373-408. [PMID: 32879702 PMCID: PMC7439452 DOI: 10.4330/wjc.v12.i8.373] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/19/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues. The sympathetic nervous system (SNS) is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes, circulating and neuronal catecholamine spillover, attenuated parasympathetic response, and augmented sympathetic outflow to the heart, kidneys and skeletal muscles. When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis, maladaptive ventricular and vascular remodeling, arrhythmogenesis, and poor prognosis in patients with HF. These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities. Therefore, this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF. Finally, special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.
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Affiliation(s)
- Josip Anđelo Borovac
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
| | - Domenico D'Amario
- Department of Cardiovascular and Thoracic Sciences, IRCCS Fondazione Policlinico A. Gemelli, Universita Cattolica Sacro Cuore, Rome 00168, Italy
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Duska Glavas
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
- Clinic for Cardiovascular Diseases, University Hospital of Split, Split 21000, Croatia
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20
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The endothelin system as target for therapeutic interventions in cardiovascular and renal disease. Clin Chim Acta 2020; 506:92-106. [DOI: 10.1016/j.cca.2020.03.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/05/2020] [Accepted: 03/05/2020] [Indexed: 12/12/2022]
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21
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Alvarez CK, Cronin E, Baker WL, Kluger J. Heart failure as a substrate and trigger for ventricular tachycardia. J Interv Card Electrophysiol 2019; 56:229-247. [PMID: 31598875 DOI: 10.1007/s10840-019-00623-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 09/06/2019] [Indexed: 02/06/2023]
Abstract
Heart failure (HF) is a major cause of morbidity and mortality with more than 5.1 million individuals affected in the USA. Ventricular tachyarrhythmias (VAs) including ventricular tachycardia and ventricular fibrillation are common in patients with heart failure. The pathophysiology of these mechanisms as well as the contribution of heart failure to the genesis of these arrhythmias is complex and multifaceted. Myocardial hypertrophy and stretch with increased preload and afterload lead to shortening of the action potential at early repolarization and lengthening of the action potential at final repolarization which can result in re-entrant ventricular tachycardia. Myocardial fibrosis and scar can create the substrate for re-entrant ventricular tachycardia. Altered calcium handling in the failing heart can lead to the development of proarrhythmic early and delayed after depolarizations. Various medications used in the treatment of HF such as loop diuretics and angiotensin converting enzyme inhibitors have not demonstrated a reduction in sudden cardiac death (SCD); however, beta-blockers (BB) are effective in reducing mortality and SCD. Amongst patients who have HF with reduced ejection fraction, the angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) has been shown to reduce cardiovascular mortality, specifically by reducing SCD, as well as death due to worsening HF. Implantable cardioverter-defibrillator (ICD) implantation in HF patients reduces the risk of SCD; however, subsequent mortality is increased in those who receive ICD shocks. Prophylactic ICD implantation reduces death from arrhythmia but does not reduce overall mortality during the acute post-myocardial infarction (MI) period (less than 40 days), for those with reduced ejection fraction and impaired autonomic dysfunction. Furthermore, although death from arrhythmias is reduced, this is offset by an increase in the mortality from non-arrhythmic causes. This article provides a review of the aforementioned mechanisms of arrhythmogenesis in heart failure; the role and impact of HF therapy such as cardiac resynchronization therapy (CRT), including the role, if any, of CRT-P and CRT-D in preventing VAs; the utility of both non-invasive parameters as well as multiple implant-based parameters for telemonitoring in HF; and the effect of left ventricular assist device implantation on VAs.
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Affiliation(s)
- Chikezie K Alvarez
- Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY, 10467, USA.
| | - Edmond Cronin
- University of Connecticut School of Medicine, Farmington, CT, USA
| | - William L Baker
- University of Connecticut School of Pharmacy, Storrs, CT, USA
| | - Jeffrey Kluger
- Hartford Healthcare Heart and Vascular Institute, Hartford Hospital, Hartford, CT, USA
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22
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Trensz F, Bortolamiol C, Kramberg M, Wanner D, Hadana H, Rey M, Strasser DS, Delahaye S, Hess P, Vezzali E, Mentzel U, Ménard J, Clozel M, Iglarz M. Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension. J Pharmacol Exp Ther 2019; 368:462-473. [PMID: 30622171 DOI: 10.1124/jpet.118.253864] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 12/27/2018] [Indexed: 03/08/2025] Open
Abstract
The endothelin (ET) system has emerged as a novel target for hypertension treatment where a medical need persists despite availability of several pharmacological classes, including renin angiotensin system (RAS) blockers. ET receptor antagonism has demonstrated efficacy in preclinical models of hypertension, especially under low-renin conditions and in hypertensive patients. We investigated the pharmacology of aprocitentan (N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-sulfamide), a potent dual ETA/ETB receptor antagonist, on blood pressure (BP) in two models of experimental hypertension: deoxycorticosterone acetate (DOCA)-salt rats (low-renin model) and spontaneously hypertensive rats [(SHR), normal renin model]. We also compared the effect of its combination with RAS blockers (valsartan and enalapril) with that of the combination of the mineraloreceptor antagonist spironolactone with the same RAS blockers on BP and renal function in hypertensive rats. Aprocitentan was more potent and efficacious in lowering BP in conscious DOCA-salt rats than in SHRs. In DOCA-salt rats, single oral doses of aprocitentan induced a dose-dependent and long-lasting BP decrease and 4-week administration of aprocitentan dose dependently decreased BP (statistically significant) and renal vascular resistance, and reduced left ventricle hypertrophy (nonsignificant). Aprocitentan was synergistic with valsartan and enalapril in decreasing BP in DOCA-salt rats and SHRs while spironolactone demonstrated additive effects with these RAS blockers. In hypertensive rats under sodium restriction and enalapril, addition of aprocitentan further decreased BP without causing renal impairment, in contrast to spironolactone. In conclusion, ETA/ETB receptor antagonism represents a promising therapeutic approach to hypertension, especially with low-renin characteristics, and could be used in combination with RAS blockers, without increasing the risk of renal impairment.
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Affiliation(s)
- Frederic Trensz
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Céline Bortolamiol
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Markus Kramberg
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Daniel Wanner
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Hakim Hadana
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Markus Rey
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Daniel S Strasser
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Stéphane Delahaye
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Patrick Hess
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Enrico Vezzali
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Ulrich Mentzel
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Joël Ménard
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Martine Clozel
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Marc Iglarz
- Drug Discovery Department, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
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23
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Naranjo M, Lo KB, Mezue K, Rangaswami J. Effects of Pulmonary Hypertension and Right Ventricular Function in Short and Long-Term Kidney Function. Curr Cardiol Rev 2019; 15:3-11. [PMID: 30306876 PMCID: PMC6367698 DOI: 10.2174/1573403x14666181008154215] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 09/22/2018] [Accepted: 09/30/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Pulmonary hypertension is not uncommon in patients with renal disease and vice versa; therefore, it influences treatments and outcomes. There is a large body of literature on pulmonary hypertension in patients with kidney disease, its prognostic implications, economic burden, and management strategies. However, the converse, namely the hemodynamic effects of pulmonary hypertension on kidney function (acute and chronic kidney injury) is less studied and described. There is also increasing interest in the effects of pulmonary hypertension on kidney transplant outcomes. The relationship is a complex phenomenon and multiple body systems and mechanisms are involved in its pathophysiology. Although the definition of pulmonary hypertension has evolved over time with the understanding of multiple interplays between the heart, lungs, kidneys, etc; there is limited evidence to provide a specific treatment strategy when kidneys and lungs are affected at the same time. Nevertheless, available evidence appears to support new therapeutics and highlights the importance of individualized approach. There is sufficient research showing that the morbidity and mortality from PH are driven by the influence of the pulmonary hemodynamic dysfunction on the kidneys. CONCLUSION This concise review focuses on the effects of pulmonary hypertension on the kidneys, including, the patho-physiological effects of pulmonary hypertension on acute kidney injury, progression of CKD, effects on kidney transplant outcomes, progression of kidney disease in situations such as post LVAD implantation and novel diagnostic indices. We believe a review of this nature will fill in an important gap in understanding the prognostic implication of pulmonary hypertension on renal disease, and help highlight this important component of the cardio-reno-pulmonary axis.
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Affiliation(s)
- Mario Naranjo
- Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA, United States
| | - Kevin Bryan Lo
- Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA, United States
| | - Kenechukwu Mezue
- Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA, United States
| | - Janani Rangaswami
- Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA, United States.,Sidney Kimmel College of Thomas Jefferson University, Philadelphia, PA, United States
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24
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Abstract
Pulmonary hypertension (PH) is a common hemodynamic evolution of heart failure (HF) with preserved or reduced ejection fraction, responsible for congestion, symptoms worsening, exercise limitation, and negative outcome. In HF of any origin, PH develops in response to a passive backward pressure transmission as result of increased left atrial pressure. Sustained pressure injury and chronic venous congestion can trigger pulmonary vasoconstriction and vascular remodeling, leading to irreversible pulmonary vascular disease, right ventricular hypertrophy, and failure. In this article, the key determinants of this "dangerous liaison" are analyzed with some digressions on related "leitmotiv" at the horizon.
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Affiliation(s)
- Marco Guazzi
- Heart Failure Unit, IRCCS Policlinico San Donato, Piazza E. Malan 2, San Donato Milanese, Milano 20097, Italy.
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25
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Lachaux M, Barrera-Chimal J, Nicol L, Rémy-Jouet I, Renet S, Dumesnil A, Wecker D, Richard V, Kolkhof P, Jaisser F, Ouvrard-Pascaud A, Mulder P. Short- and long-term administration of the non-steroidal mineralocorticoid receptor antagonist finerenone opposes metabolic syndrome-related cardio-renal dysfunction. Diabetes Obes Metab 2018; 20:2399-2407. [PMID: 29862614 DOI: 10.1111/dom.13393] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 05/23/2018] [Accepted: 05/25/2018] [Indexed: 12/22/2022]
Abstract
AIM To determine whether non-steroidal mineralocorticoid receptor (MR) antagonists oppose metabolic syndrome-related end-organ, i.e. cardiac, damage. MATERIALS AND METHODS In Zucker fa/fa rats, a rat model of metabolic syndrome, we assessed the effects of the non-steroidal MR antagonist finerenone (oral 2 mg/kg/day) on left ventricular (LV) function, haemodynamics and remodelling (using echocardiography, magnetic resonance imaging and biochemical methods). RESULTS Long-term (90 days) finerenone modified neither systolic blood pressure nor heart rate, but reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relationship, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relationship. Simultaneously, long-term finerenone reduced both LV systolic and diastolic diameters, associated with reductions in LV weight and LV collagen density, while proteinuria and renal nGAL expression were reduced. Short-term (7 days) finerenone improved LV haemodynamics and reduced LV systolic diameter, without modifying LV diastolic diameter. Moreover, short-term finerenone increased myocardial tissue perfusion and reduced myocardial reactive oxygen species, while plasma nitrite levels, an indicator of nitric oxide (NO) bio-availability, were increased. CONCLUSIONS In rats with metabolic syndrome, the non-steroidal MR antagonist finerenone opposed metabolic syndrome-related diastolic cardiac dysfunction and nephropathy. This involved acute effects, such as improved myocardial perfusion, reduced oxidative stress/increased NO bioavailability, as well as long-term effects, such as modifications in the myocardial structure.
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Affiliation(s)
- Marianne Lachaux
- Normandie Univ, UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096, FHU- REMOD-VHF, 76000 Rouen, France
| | | | - Lionel Nicol
- Normandie Univ, UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096, FHU- REMOD-VHF, 76000 Rouen, France
| | - Isabelle Rémy-Jouet
- Normandie Univ, UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096, FHU- REMOD-VHF, 76000 Rouen, France
| | - Sylvanie Renet
- Normandie Univ, UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096, FHU- REMOD-VHF, 76000 Rouen, France
| | - Anais Dumesnil
- Normandie Univ, UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096, FHU- REMOD-VHF, 76000 Rouen, France
| | | | - Vincent Richard
- Normandie Univ, UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096, FHU- REMOD-VHF, 76000 Rouen, France
| | | | - Frederic Jaisser
- Institut National de la Santé et de la Recherche Médicale U1138, Paris, France
| | - Antoine Ouvrard-Pascaud
- Normandie Univ, UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096, FHU- REMOD-VHF, 76000 Rouen, France
| | - Paul Mulder
- Normandie Univ, UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096, FHU- REMOD-VHF, 76000 Rouen, France
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26
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Ceylan AF, Wang S, Kandadi MR, Chen J, Hua Y, Pei Z, Nair S, Ren J. Cardiomyocyte-specific knockout of endothelin receptor a attenuates obesity cardiomyopathy. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3339-3352. [DOI: 10.1016/j.bbadis.2018.07.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 07/14/2018] [Accepted: 07/16/2018] [Indexed: 12/20/2022]
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27
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Frangogiannis NG. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Aspects Med 2018; 65:70-99. [PMID: 30056242 DOI: 10.1016/j.mam.2018.07.001] [Citation(s) in RCA: 559] [Impact Index Per Article: 79.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 07/23/2018] [Indexed: 12/13/2022]
Abstract
Cardiac fibrosis is a common pathophysiologic companion of most myocardial diseases, and is associated with systolic and diastolic dysfunction, arrhythmogenesis, and adverse outcome. Because the adult mammalian heart has negligible regenerative capacity, death of a large number of cardiomyocytes results in reparative fibrosis, a process that is critical for preservation of the structural integrity of the infarcted ventricle. On the other hand, pathophysiologic stimuli, such as pressure overload, volume overload, metabolic dysfunction, and aging may cause interstitial and perivascular fibrosis in the absence of infarction. Activated myofibroblasts are the main effector cells in cardiac fibrosis; their expansion following myocardial injury is primarily driven through activation of resident interstitial cell populations. Several other cell types, including cardiomyocytes, endothelial cells, pericytes, macrophages, lymphocytes and mast cells may contribute to the fibrotic process, by producing proteases that participate in matrix metabolism, by secreting fibrogenic mediators and matricellular proteins, or by exerting contact-dependent actions on fibroblast phenotype. The mechanisms of induction of fibrogenic signals are dependent on the type of primary myocardial injury. Activation of neurohumoral pathways stimulates fibroblasts both directly, and through effects on immune cell populations. Cytokines and growth factors, such as Tumor Necrosis Factor-α, Interleukin (IL)-1, IL-10, chemokines, members of the Transforming Growth Factor-β family, IL-11, and Platelet-Derived Growth Factors are secreted in the cardiac interstitium and play distinct roles in activating specific aspects of the fibrotic response. Secreted fibrogenic mediators and matricellular proteins bind to cell surface receptors in fibroblasts, such as cytokine receptors, integrins, syndecans and CD44, and transduce intracellular signaling cascades that regulate genes involved in synthesis, processing and metabolism of the extracellular matrix. Endogenous pathways involved in negative regulation of fibrosis are critical for cardiac repair and may protect the myocardium from excessive fibrogenic responses. Due to the reparative nature of many forms of cardiac fibrosis, targeting fibrotic remodeling following myocardial injury poses major challenges. Development of effective therapies will require careful dissection of the cell biological mechanisms, study of the functional consequences of fibrotic changes on the myocardium, and identification of heart failure patient subsets with overactive fibrotic responses.
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Affiliation(s)
- Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer G46B, Bronx, NY, 10461, USA.
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28
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Hernández M, Wicz S, Santamaría MH, Corral RS. Curcumin exerts anti-inflammatory and vasoprotective effects through amelioration of NFAT-dependent endothelin-1 production in mice with acute Chagas cardiomyopathy. Mem Inst Oswaldo Cruz 2018; 113:e180171. [PMID: 30020318 PMCID: PMC6048587 DOI: 10.1590/0074-02760180171] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 06/11/2018] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The anti-inflammatory and cardioprotective properties of curcumin (Cur), a natural polyphenolic flavonoid isolated from the rhizomes of Curcuma longa, are increasingly considered to have beneficial effects on the progression of Chagas heart disease, caused by the protozoan parasite Trypanosoma cruzi. OBJECTIVE To evaluate the effects of oral therapy with Cur on T. cruzi-mediated cardiovasculopathy in acutely infected mice and analyse the in vitro response of parasite-infected human microvascular endothelial cells treated with this phytochemical. METHODS Inflammation of heart vessels from Cur-treated and untreated infected mice were analysed by histology, with benznidazole (Bz) as the reference compound. Parasitaemia was monitored by the direct method. Capillary permeability was visualised by Evans-blue assay. Myocardial ET-1, IL-6, and TNF-α mRNA expressions were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Microvascular endothelial HMEC-1 cells were infected in vitro with or without addition of Cur or Bz. Induction of the Ca2+/NFAT pathway was assessed by fluorometry, immunoblotting, and reporter assay. FINDINGS Oral Cur therapy of recently infected mice reduced inflammatory cell infiltration of myocardial arteries without lowering parasite levels. Compared to that of the phosphate-buffered saline-receiving group, hearts from Cur-treated mice showed significantly decreased vessel inflammation scores (p < 0.001), vascular permeabilities (p < 0.001), and levels of IL-6/TNF-α (p < 0.01) and ET-1 (p < 0.05) mRNA. Moreover, Cur significantly (p < 0.05 for transcript; p < 0.01 for peptide) downregulated ET-1 secretion from infected HMEC-1 cells. Remarkably, Cur addition significantly (p < 0.05 at 27.0 μM) interfered with T. cruzi-dependent activation of the Ca2+/NFATc1 signalling pathway that promotes generation of inflammatory agents in HMEC-1 cells. CONCLUSIONS Oral treatment with Cur dampens cardiovasculopathy in acute Chagas mice. Cur impairs the Ca2+/NFATc1-regulated release of ET-1 from T. cruzi-infected vascular endothelium. These findings identify new perspectives for exploring the potential of Cur-based interventions to ameliorate Chagas heart disease.
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Affiliation(s)
- Matías Hernández
- Universidad Nacional de San Luis, Facultad de Química, Bioquímica y Farmacia, Laboratorio de Biomedicina Molecular, San Luis, Argentina
| | - Susana Wicz
- Universidad Nacional de San Luis, Facultad de Química, Bioquímica y Farmacia, Laboratorio de Biomedicina Molecular, San Luis, Argentina
| | - Miguel H Santamaría
- Centro de Estudios Metabólicos, Laboratorio de Biología Experimental, Santander, Spain
| | - Ricardo S Corral
- Hospital de Niños Dr Ricardo Gutiérrez, Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas, Servicio de Parasitología-Chagas, Ciudad Autónoma de Buenos Aires, Argentina
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29
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Packer M, McMurray JJV, Krum H, Kiowski W, Massie BM, Caspi A, Pratt CM, Petrie MC, DeMets D, Kobrin I, Roux S, Swedberg K. Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the ENABLE Trials. JACC-HEART FAILURE 2018; 5:317-326. [PMID: 28449795 DOI: 10.1016/j.jchf.2017.02.021] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 02/16/2017] [Accepted: 02/19/2017] [Indexed: 01/13/2023]
Abstract
OBJECTIVES The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. BACKGROUND Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. METHODS In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction <35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure. RESULTS Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure. CONCLUSIONS Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas.
| | - John J V McMurray
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Henry Krum
- Monash University, Centre of Cardiovascular Research and Education in Therapeutics, Melbourne, Australia
| | | | - Barry M Massie
- University of California at San Francisco, San Francisco, California
| | | | - Craig M Pratt
- Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas
| | - Mark C Petrie
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | | | | | | | - Karl Swedberg
- Department of Molecular and Clinical Medicine, University of Goteborg, Goteborg, Sweden; National Heart and Lung Institute, Imperial College, London, United Kingdom
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30
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Harouki N, Nicol L, Remy-Jouet I, Henry JP, Dumesnil A, Lejeune A, Renet S, Golding F, Djerada Z, Wecker D, Bolduc V, Bouly M, Roussel J, Richard V, Mulder P. The IL-1β Antibody Gevokizumab Limits Cardiac Remodeling and Coronary Dysfunction in Rats With Heart Failure. JACC Basic Transl Sci 2017; 2:418-430. [PMID: 30062160 PMCID: PMC6034492 DOI: 10.1016/j.jacbts.2017.06.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 06/06/2017] [Accepted: 06/08/2017] [Indexed: 12/31/2022]
Abstract
Immediate IL-1β antibody gevokizumab administration reduces ischemia/reperfusion related infarct size. Immediate and late IL-1β antibody gevokizumab administration improves heart failure related left ventricular remodeling. IL-1β antibody gevokizumab improves heart failure related coronary dysfunction. This study reports preclinical data showing that the interleukin (IL)-1β modulation is a new promising target in the pathophysiological context of heart failure. Indeed, in nondiabetic Wistar and diabetic Goto-Kakizaki rats with chronic heart failure induced by myocardial infarction, administration of the IL-1β antibody gevokizumab improves ‘surrogate’ markers of survival (i.e., left ventricular remodeling, hemodynamics, and function as well as coronary function). However, whether IL-1β modulation per se or in combination with standard treatments of heart failure improves long-term outcome in human heart failure remains to be determined.
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Key Words
- GK, Goto-Kakisaki
- I/R, ischemia/reperfusion
- IL, interleukin
- IL-1β
- LV, left ventricle/ventricular
- LVEDP, left ventricular end-diastolic pressure
- LVEDPV, left ventricular end-diastolic pressure–volume relationship
- LVESP, left ventricular end-systolic pressure
- LVESPVR, left ventricular end-systolic pressure–volume relationship
- ROS, reactive oxygen species
- SOD, superoxide dismutase
- cardiovascular function
- heart failure
- ischemia/reperfusion
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Affiliation(s)
- Najah Harouki
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France
| | - Lionel Nicol
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France.,Plateau d'Imagerie CardioThoracique de l'Université de Rouen, Rouen, France
| | - Isabelle Remy-Jouet
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France
| | - Jean-Paul Henry
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France
| | - Anais Dumesnil
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France
| | - Annie Lejeune
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France
| | - Sylvanie Renet
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France
| | - Francesca Golding
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France
| | - Zoubir Djerada
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France.,Pharmacology Department, Centre Hospitalier Universitaire de Reims, Reims, France
| | | | - Virginie Bolduc
- Institut de Recherches Internationales Servier, Suresnes, France
| | - Muriel Bouly
- Institut de Recherches Internationales Servier, Suresnes, France
| | - Jerome Roussel
- Institut de Recherches Internationales Servier, Suresnes, France
| | - Vincent Richard
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France
| | - Paul Mulder
- INSERM U1096, Rouen, France.,Normandy University, IRIB, Rouen, France.,Unité de formation et de recherche de Médecine et Pharmacie, Rouen University, Rouen, France.,Plateau d'Imagerie CardioThoracique de l'Université de Rouen, Rouen, France
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Phosri S, Arieyawong A, Bunrukchai K, Parichatikanond W, Nishimura A, Nishida M, Mangmool S. Stimulation of Adenosine A 2B Receptor Inhibits Endothelin-1-Induced Cardiac Fibroblast Proliferation and α-Smooth Muscle Actin Synthesis Through the cAMP/Epac/PI3K/Akt-Signaling Pathway. Front Pharmacol 2017; 8:428. [PMID: 28713274 PMCID: PMC5492828 DOI: 10.3389/fphar.2017.00428] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 06/15/2017] [Indexed: 12/19/2022] Open
Abstract
Background and Purpose: Cardiac fibrosis is characterized by an increase in fibroblast proliferation, overproduction of extracellular matrix proteins, and the formation of myofibroblast that express α-smooth muscle actin (α-SMA). Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac fibrosis. Overstimulation of endothelin receptors induced cell proliferation, collagen synthesis, and α-SMA expression in cardiac fibroblasts. Although adenosine was shown to have cardioprotective effects, the molecular mechanisms by which adenosine A2 receptor inhibit ET-1-induced fibroblast proliferation and α-SMA expression in cardiac fibroblasts are not clearly identified. Experimental Approach: This study aimed at evaluating the mechanisms of cardioprotective effects of adenosine receptor agonist in rat cardiac fibroblast by measurement of cell proliferation, and mRNA and protein levels of α-SMA. Key results: Stimulation of adenosine subtype 2B (A2B) receptor resulted in the inhibition of ET-1-induced fibroblast proliferation, and a reduction of ET-1-induced α-SMA expression that is dependent on cAMP/Epac/PI3K/Akt signaling pathways in cardiac fibroblasts. The data in this study confirm a critical role for Epac signaling on A2B receptor-mediated inhibition of ET-1-induced cardiac fibrosis via PI3K and Akt activation. Conclusion and Implications: This is the first work reporting a novel signaling pathway for the inhibition of ET-1-induced cardiac fibrosis mediated through the A2B receptor. Thus, A2B receptor agonists represent a promising perspective as therapeutic targets for the prevention of cardiac fibrosis.
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Affiliation(s)
- Sarawuth Phosri
- Department of Pharmacology, Faculty of Pharmacy, Mahidol UniversityBangkok, Thailand
| | - Ajaree Arieyawong
- Department of Pharmacology, Faculty of Pharmacy, Mahidol UniversityBangkok, Thailand
| | - Kwanchai Bunrukchai
- Department of Pharmacology, Faculty of Pharmacy, Mahidol UniversityBangkok, Thailand
| | | | - Akiyuki Nishimura
- Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural SciencesAichi, Japan
| | - Motohiro Nishida
- Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural SciencesAichi, Japan.,Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu UniversityFukuoka, Japan.,Precursory Research for Embryonic Science and Technology, Japan Science and Technology AgencyKawaguchi, Japan
| | - Supachoke Mangmool
- Department of Pharmacology, Faculty of Pharmacy, Mahidol UniversityBangkok, Thailand
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32
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Xiong B, Nie D, Cao Y, Zou Y, Yao Y, Tan J, Qian J, Rong S, Wang C, Huang J. Clinical and Hemodynamic Effects of Endothelin Receptor Antagonists in Patients With Heart Failure. Int Heart J 2017; 58:400-408. [PMID: 28539568 DOI: 10.1536/ihj.16-307] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The clinical benefit of endothelin receptor antagonists (ERA) for the management of heart failure (HF) remains controversial. To examine this question, we performed a meta-analysis of randomized controlled trials (RCTs) to investigate the clinical and hemodynamic effects of ERA in HF patients.We searched the PubMed, Medline, Embase, and Cochrane Library from inception to March 20, 2016 to identify the pertinent studies. Risk ratio (RR) and weighted mean difference (WMD) were calculated using a fixed or random effect model.A total of 15 RCTs with 3,624 HF patients were included. Compared with control groups, ERA might not improve the mortality (RR 1.12, 95%CI 0.81 to 1.54, P = 0.51) or incidence of worsening HF or cardiovascular events (WHF/ CVE) (RR 1.06, 95%CI 0.94 to 1.19, P = 0.35) in HF patients. Subgroup analysis also suggested that neither nonselective nor selective ERAs had an impact on mortality and WHF/CVE. However, the hemodynamic variables of HF patients, including cardiac index (WMD 0.32, 95%CI 0.22 to 0.43, P < 0.01), pulmonary capillary wedge pressure (WMD -3.10, 95%CI -3.99 to -2.20, P < 0.01), mean pulmonary arterial pressure (WMD -4.42, 95%CI -5.50 to -3.33, P < 0.01), systemic vascular resistance (WMD -276.35, 95%CI -399.62 to -153.09, P < 0.01), and pulmonary vascular resistance (WMD -69.42, 95%CI -105.33 to -33.52, P < 0.01) were significantly improved by ERA.In conclusion, this meta-analysis suggests that ERA therapy could effectively improve cardiac output and pulmonary and systemic hemodynamics, but with less benefit to the clinical outcomes of HF patients.
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Affiliation(s)
- Bo Xiong
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University
| | - Dan Nie
- Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College
| | - Yin Cao
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University
| | - Yanke Zou
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University
| | - Yuanqing Yao
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University
| | - Jie Tan
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University
| | - Jun Qian
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University
| | - Shunkang Rong
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University
| | - Chunbin Wang
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University
| | - Jing Huang
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University
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Olivier A, Girerd N, Michel JB, Ketelslegers JM, Fay R, Vincent J, Bramlage P, Pitt B, Zannad F, Rossignol P. Combined baseline and one-month changes in big endothelin-1 and brain natriuretic peptide plasma concentrations predict clinical outcomes in patients with left ventricular dysfunction after acute myocardial infarction: Insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study. Int J Cardiol 2017; 241:344-350. [PMID: 28284500 DOI: 10.1016/j.ijcard.2017.02.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 01/14/2017] [Accepted: 02/03/2017] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI. METHODS In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients. RESULTS When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint). CONCLUSIONS Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies. KEY MESSAGES In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies.
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Affiliation(s)
- A Olivier
- Inserm, CIC-P 14-33, U 116, CHU Nancy, France; University of Lorraine, France; F-CRIN INI-CRCT, Nancy, France; Department of Cardiovascular Disease, Institut Lorrain du Coeur et des Vaisseaux, Nancy University Hospital, Nancy, France.
| | - N Girerd
- Inserm, CIC-P 14-33, U 116, CHU Nancy, France; University of Lorraine, France; F-CRIN INI-CRCT, Nancy, France
| | - J B Michel
- Inserm, UMRS 1148 University Paris Diderot, Paris, France
| | | | - R Fay
- Inserm, CIC-P 14-33, U 116, CHU Nancy, France; University of Lorraine, France; F-CRIN INI-CRCT, Nancy, France
| | | | - P Bramlage
- Institute for Cardiovascular Pharmacology and Epidemiology, Mahlow, Germany
| | - B Pitt
- University of Michigan, School of Medicine, Ann Arbor, MI, USA
| | - F Zannad
- Inserm, CIC-P 14-33, U 116, CHU Nancy, France; University of Lorraine, France; F-CRIN INI-CRCT, Nancy, France; Department of Cardiovascular Disease, Institut Lorrain du Coeur et des Vaisseaux, Nancy University Hospital, Nancy, France
| | - P Rossignol
- Inserm, CIC-P 14-33, U 116, CHU Nancy, France; University of Lorraine, France; F-CRIN INI-CRCT, Nancy, France
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Benza R, Mathai S, Nathan SD. sGC stimulators: Evidence for riociguat beyond groups 1 and 4 pulmonary hypertension. Respir Med 2017; 122 Suppl 1:S28-S34. [DOI: 10.1016/j.rmed.2016.11.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 10/10/2016] [Accepted: 11/13/2016] [Indexed: 01/03/2023]
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Abstract
A key feature of chronic heart failure (HF) is the sustained activation of endogenous neurohormonal systems in response to impaired cardiac pumping and/or filling properties. The clinical use of neurohormonal blockers has revolutionised the care of HF patients over the past three decades. Drug therapy that is active against imbalance in both the autonomic and renin-angiotensin-aldosterone systems consistently reduces morbidity and mortality in chronic HF with reduced left ventricular ejection fraction and in sinus rhythm. This article provides an assessment of the major neurohormonal systems and their therapeutic blockade in patients with chronic HF.
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Affiliation(s)
- Thomas G von Lueder
- Department of Cardiology, Oslo University Hospital UllevÅl, Oslo, Norway.,Monash Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia and Alfred Hospital, Melbourne, Australia
| | - Dipak Kotecha
- Monash Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia and Alfred Hospital, Melbourne, Australia.,University of Birmingham Institute of Cardiovascular Sciences, Birmingham, UK
| | - Dan Atar
- Department of Cardiology, Oslo University Hospital UllevÅl, Oslo, Norway
| | - Ingrid Hopper
- Monash Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia and Alfred Hospital, Melbourne, Australia
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Pilot Study of Endothelin Receptor Blockade in Heart Failure with Diastolic Dysfunction and Pulmonary Hypertension (BADDHY-Trial). Heart Lung Circ 2016; 26:433-441. [PMID: 27816421 DOI: 10.1016/j.hlc.2016.09.004] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 07/09/2016] [Accepted: 09/02/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND In this multi-centre, randomised, placebo-controlled pilot trial, we investigated the clinical and haemodynamic effects of the endothelin-receptor blocker Bosentan in patients with heart failure, preserved ejection fraction and pulmonary hypertension (PH-HFpEF). MATERIALS AND METHODS Eligible patients received either 12 weeks of Bosentan therapy, or a placebo drug. Patients were thereafter followed for a further period of 12 weeks without the study medication. At three points during the study (study Commencement, Week 12 and Week 24), a six-minute walk test (6MWT), echocardiographic and laboratory assessments were performed, as well as a quality of life survey. Right heart catheterisation (RHC) was undertaken at commencement only. The study was aborted early, after an interim analysis favoured the placebo. RESULTS Six-minute walk distance (6MWD) did not change in the Bosentan group (309.7±96.3m (Commencement), 317.0±126.1m (Week 12), 307.0±84.4m (Week 24); p=0.86), but almost reached statistical significance in the placebo group from 328.8±79.6m, to 361.6±98.2m and 384.0±74.9m (Week 24); p=0.075. In the placebo group, estimated systolic pulmonary artery pressure (measured via echocardiography) significantly decreased (from 62.3±16.7mmHg [Commencement], 45.3±13.9mmHg [Week 12], to 44.6±14.5mmHg [Week 24]; p=0.014) as did right atrial pressure (13.1±5.3 [Commencement], 10.0±3.8 [Week 12], to 9.4±3.2 [Week 24]; p=0.046). CONCLUSION Despite this study's limited sample size and premature cessation, it nevertheless suggests that endothelin receptor blockade in patients with PH-HFpEF may have no beneficial effects and could even be detrimental in comparison to a placebo.
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Chan EAW, Buckley B, Farraj AK, Thompson LC. The heart as an extravascular target of endothelin-1 in particulate matter-induced cardiac dysfunction. Pharmacol Ther 2016; 165:63-78. [PMID: 27222357 PMCID: PMC6390286 DOI: 10.1016/j.pharmthera.2016.05.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Exposure to particulate matter air pollution has been causally linked to cardiovascular disease in humans. Several broad and overlapping hypotheses describing the biological mechanisms by which particulate matter exposure leads to cardiovascular disease have been explored, although linkage with specific factors or genes remains limited. These hypotheses may or may not also lead to particulate matter-induced cardiac dysfunction. Evidence pointing to autocrine/paracrine signaling systems as modulators of cardiac dysfunction has increased interest in the emerging role of endothelins as mediators of cardiac function following particulate matter exposure. Endothelin-1, a well-described small peptide expressed in the pulmonary and cardiovascular systems, is best known for its ability to constrict blood vessels, although it can also induce extravascular effects. Research on the role of endothelins in the context of air pollution has largely focused on vascular effects, with limited investigation of responses resulting from the direct effects of endothelins on cardiac tissue. This represents a significant knowledge gap in air pollution health effects research, given the abundance of endothelin receptors found on cardiac tissue and the ability of endothelin-1 to modulate cardiac contractility, heart rate, and rhythm. The plausibility of endothelin-1 as a mediator of particulate matter-induced cardiac dysfunction is further supported by the therapeutic utility of certain endothelin receptor antagonists. The present review examines the possibility that endothelin-1 release caused by exposure to PM directly modulates extravascular effects on the heart, deleteriously altering cardiac function.
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Affiliation(s)
- Elizabeth A W Chan
- Oak Ridge Institute for Science and Education (ORISE) Fellow at the National Center for Environmental Assessment, U.S. Environmental Protection Agency (EPA), Research Triangle Park, NC, USA
| | - Barbara Buckley
- National Center for Environmental Assessment, U.S. EPA, Research Triangle Park, NC, USA
| | - Aimen K Farraj
- Environmental Public Health Division, U.S. EPA, Research Triangle Park, NC, USA
| | - Leslie C Thompson
- Environmental Public Health Division, U.S. EPA, Research Triangle Park, NC, USA.
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Vascular Effects of Endothelin Receptor Antagonists Depends on Their Selectivity for ETA Versus ETB Receptors and on the Functionality of Endothelial ETB Receptors. J Cardiovasc Pharmacol 2016; 66:332-7. [PMID: 25992919 PMCID: PMC4598072 DOI: 10.1097/fjc.0000000000000283] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The goal of this study was to characterize the role of Endothelin (ET) type B receptors (ETB) on vascular function in healthy and diseased conditions and demonstrate how it affects the pharmacological activity of ET receptor antagonists (ERAs).
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Selective Heart Rate Reduction Improves Metabolic Syndrome-related Left Ventricular Diastolic Dysfunction. J Cardiovasc Pharmacol 2016. [PMID: 26222991 DOI: 10.1097/fjc.0000000000000294] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Enhanced heart rate observed in metabolic syndrome (MS) contributes to the deterioration of left ventricular (LV) function via impaired LV filling and relaxation, increased myocardial O2 consumption, and reduced coronary perfusion. However, whether heart rate reduction (HRR) opposes LV dysfunction observed in MS is unknown. METHODS We assessed in Zucker fa/fa rats, a rat model of MS, the cardiovascular effects of HRR induced by the If current inhibitor S38844 (3 mg · kg(-1) · d(-1)). RESULTS Delayed short-term (4 days) and long-term (90 days) HRR induced by S38844 reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relation, increased myocardial tissue perfusion, decreased myocardial oxidized glutathione levels, and preserved cardiac output, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relation, although only long-term S38844 opposed LV collagen accumulation. Long-term S38844 improved flow-induced endothelium-dependent dilatation of mesenteric arteries, while metabolic parameters, such as plasma glucose levels, and Hb1c, were never modified. CONCLUSIONS In rats with MS, HRR induced by the If inhibitor S38844 improved LV diastolic function and endothelium-dependent vascular dilatation, independent from modifications in metabolic status. Moreover, this improvement in cardiac function involves not only immediate effects such as improved myocardial perfusion and reduced oxidative stress but also long-term effects such as modifications in the myocardial structure.
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40
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Zhu B, Liu K, Yang C, Qiao Y, Li Z. Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling. Can J Physiol Pharmacol 2016; 94:1349-1355. [PMID: 27733054 DOI: 10.1139/cjpp-2016-0103] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cardiac remodeling is the pathological basis of various cardiovascular diseases. In this study, we found gender-related differences in β-adrenergic receptor (AR)-mediated pathological cardiac remodeling. Cardiac remodeling model was established by subcutaneous injection of isoprenaline (ISO) for 14 days. Heart rate (HR), mean arterial pressure (MAP), and echocardiography were obtained on 7th and 14th days during ISO administration. Myocardial cross-sectional area and the ratio of heart mass to tibia length (HM/TL) were detected to assess cardiac hypertrophy. Picro-Sirius red staining (picric acid + Sirius red F3B) was used to evaluate cardiac fibrosis. Myocardial capillary density was assessed by immunohistochemistry for von Willebrand factor. Further, real-time PCR was used to measure the expression of β1-AR and β2-AR. Results showed that ISO induced cardiac remodeling, the extent of which was different between female and male mice. The extent of increase in cardiac wall thickness, myocardial cross-sectional area, and collagen deposition in females was less than that in males. However, no gender-related difference was observed in HR, MAP, cardiac function, and myocardial capillary density. The distinctive decrease of β2-AR expression, rather than a decrease of β1-AR expression, seemed to result in gender-related differences in cardiac remodeling.
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Affiliation(s)
- Baoling Zhu
- Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, People's Republic of China.,Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, People's Republic of China
| | - Kai Liu
- Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, People's Republic of China.,Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, People's Republic of China
| | - Chengzhi Yang
- Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, People's Republic of China.,Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, People's Republic of China
| | - Yuhui Qiao
- Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, People's Republic of China.,Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, People's Republic of China
| | - Zijian Li
- Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, People's Republic of China.,Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, People's Republic of China
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Targeting the ROS-HIF-1-endothelin axis as a therapeutic approach for the treatment of obstructive sleep apnea-related cardiovascular complications. Pharmacol Ther 2016; 168:1-11. [PMID: 27492897 DOI: 10.1016/j.pharmthera.2016.07.010] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 07/08/2016] [Indexed: 12/12/2022]
Abstract
Obstructive sleep apnea (OSA) is now recognized as an independent and important risk factor for cardiovascular diseases such as hypertension, coronary heart disease, heart failure and stroke. Clinical and experimental data have confirmed that intermittent hypoxia is a major contributor to these deleterious consequences. The repetitive occurrence of hypoxia-reoxygenation sequences generates significant amounts of free radicals, particularly in moderate to severe OSA patients. Moreover, in addition to hypoxia, reactive oxygen species (ROS) are potential inducers of the hypoxia inducible transcription factor-1 (HIF-1) that promotes the transcription of numerous adaptive genes some of which being deleterious for the cardiovascular system, such as the endothelin-1 gene. This review will focus on the involvement of the ROS-HIF-1-endothelin signaling pathway in OSA and intermittent hypoxia and discuss current and potential therapeutic approaches targeting this pathway to treat or prevent cardiovascular disease in moderate to severe OSA patients.
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Boss C, Bolli MH, Gatfield J. From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective. Bioorg Med Chem Lett 2016; 26:3381-94. [DOI: 10.1016/j.bmcl.2016.06.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 06/03/2016] [Accepted: 06/06/2016] [Indexed: 11/24/2022]
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Bonsu KO, Owusu IK, Buabeng KO, Reidpath DD, Kadirvelu A. Review of novel therapeutic targets for improving heart failure treatment based on experimental and clinical studies. Ther Clin Risk Manag 2016; 12:887-906. [PMID: 27350750 PMCID: PMC4902145 DOI: 10.2147/tcrm.s106065] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) is a major public health priority due to its epidemiological transition and the world's aging population. HF is typified by continuous loss of contractile function with reduced, normal, or preserved ejection fraction, elevated vascular resistance, fluid and autonomic imbalance, and ventricular dilatation. Despite considerable advances in the treatment of HF over the past few decades, mortality remains substantial. Pharmacological treatments including β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists have been proven to prolong the survival of patients with HF. However, there are still instances where patients remain symptomatic, despite optimal use of existing therapeutic agents. This understanding that patients with chronic HF progress into advanced stages despite receiving optimal treatment has increased the quest for alternatives, exploring the roles of additional pathways that contribute to the development and progression of HF. Several pharmacological targets associated with pathogenesis of HF have been identified and novel therapies have emerged. In this work, we review recent evidence from proposed mechanisms to the outcomes of experimental and clinical studies of the novel pharmacological agents that have emerged for the treatment of HF.
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Affiliation(s)
- Kwadwo Osei Bonsu
- School of Medicine and Health Sciences, Monash University Sunway Campus, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya, Selangor, Malaysia
- Accident and Emergency Directorate, Komfo Anokye Teaching Hospital, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Isaac Kofi Owusu
- Department of Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Kwame Ohene Buabeng
- Department of Clinical and Social Pharmacy, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Daniel Diamond Reidpath
- School of Medicine and Health Sciences, Monash University Sunway Campus, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya, Selangor, Malaysia
| | - Amudha Kadirvelu
- School of Medicine and Health Sciences, Monash University Sunway Campus, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya, Selangor, Malaysia
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Bouvet M, Dubois-Deruy E, Alayi TD, Mulder P, El Amranii M, Beseme O, Amouyel P, Richard V, Tomavo S, Pinet F. Increased level of phosphorylated desmin and its degradation products in heart failure. Biochem Biophys Rep 2016; 6:54-62. [PMID: 28955862 PMCID: PMC5600436 DOI: 10.1016/j.bbrep.2016.02.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 02/11/2016] [Accepted: 02/25/2016] [Indexed: 01/03/2023] Open
Abstract
Although several risk factors such as infarct size have been identified, the progression/severity of heart failure (HF) remains difficult to predict in clinical practice. Using an experimental rat model of ischemic HF and phosphoproteomic technology, we found an increased level of phosphorylated desmin in the left ventricle (LV) of HF-rats. The purpose of the present work is to assess whether desmin is a circulating or only a tissue biomarker of HF. We used several antibodies in order to detect desmin, its proteolytic fragments and its phosphorylated form in LV and plasma by western blot, phosphate affinity electrophoresis, mass spectrometry and immunofluorescence. Plasma was treated with combinatorial peptide ligand library or depleted for albumin and immunoglobulins to increase the sensitivity of detection. We found a 2-fold increased serine-desmin phosphorylation in the LV of HF-rats, mainly in the insoluble fraction, suggesting the formation of desmin aggregates. Desmin cleavage products were also detected in the LV of HF rats, indicating that the increased phosphorylation of desmin results in more susceptibility to proteolytic activity, likely mediated by calpain activity. The native desmin and its degradation products were undetectable in the plasma of rat, mouse or human. These data suggest the potential of serine-phosphorylated form of desmin and its degradation products, but not of desmin itself, as tissue but not circulating biomarkers of HF.
Desmin is mainly expressed in insoluble fraction of rat left ventricle. In experimental heart failure, desmin is highly phosphorylated in serine. Desmin and its degradation products are not detected in plasma.
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Affiliation(s)
- Marion Bouvet
- INSERM, U1167, University Lille, Institut Pasteur de Lille, F-59000 Lille, France
| | - Emilie Dubois-Deruy
- INSERM, U1167, University Lille, Institut Pasteur de Lille, F-59000 Lille, France
| | - Tchilabalo Dilezitoko Alayi
- University Lille, CNRS UMR8204, INSERM, U1019, Institut Pasteur de Lille, Plateforme de Protéomique et des Peptides Modifiés (P3M), F-59000 Lille, France
| | - Paul Mulder
- INSERM, U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, F-76000 Rouen, France
| | - Myriam El Amranii
- University Lille, CNRS UMR8204, INSERM, U1019, Institut Pasteur de Lille, Plateforme de Protéomique et des Peptides Modifiés (P3M), F-59000 Lille, France
| | - Olivia Beseme
- INSERM, U1167, University Lille, Institut Pasteur de Lille, F-59000 Lille, France
| | - Philippe Amouyel
- INSERM, U1167, University Lille, Institut Pasteur de Lille, Centre Hospitalier Régional et Universitaire de Lille, F-59000 Lille, France
| | - Vincent Richard
- INSERM, U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, F-76000 Rouen, France
| | - Stanislas Tomavo
- University Lille, CNRS UMR8204, INSERM, U1019, Institut Pasteur de Lille, Plateforme de Protéomique et des Peptides Modifiés (P3M), F-59000 Lille, France
| | - Florence Pinet
- INSERM, U1167, University Lille, Institut Pasteur de Lille, F-59000 Lille, France
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Czubryt MP. Going the distance: Epigenetic regulation of endothelial endothelin-1 controls cardiac hypertrophy. J Mol Cell Cardiol 2015; 82:60-2. [DOI: 10.1016/j.yjmcc.2015.02.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 02/27/2015] [Indexed: 01/08/2023]
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Dubois-Deruy E, Belliard A, Mulder P, Bouvet M, Smet-Nocca C, Janel S, Lafont F, Beseme O, Amouyel P, Richard V, Pinet F. Interplay between troponin T phosphorylation and O-N-acetylglucosaminylation in ischaemic heart failure. Cardiovasc Res 2015; 107:56-65. [PMID: 25916824 DOI: 10.1093/cvr/cvv136] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Accepted: 04/15/2015] [Indexed: 11/13/2022] Open
Abstract
AIMS Previous studies have reported that decreased serine 208 phosphorylation of troponin T (TnTpSer208) is associated with ischaemic heart failure (HF), but the molecular mechanisms and functional consequences of these changes are unknown. The aim of this study was to characterize the balance between serine phosphorylation and O-N-acetylglucosaminylation (O-GlcNAcylation) of TnT in HF, its mechanisms, and the consequences of modulating these post-translational modifications. METHODS AND RESULTS Decreased TnTpSer208 levels in the left ventricles of HF male Wistar rats were associated with reduced expression of PKCε but not of other cardiac PKC isoforms. In both isolated perfused rat hearts and cultured neonatal cardiomyocytes, the PKCε inhibitor εV1-2 decreased TnTpSer208 and simultaneously decreased cardiac contraction in isolated hearts and beating amplitude in neonatal cardiomyocytes (measured by atomic force microscopy). Down-regulating PKCε by silencing RNA (siRNA) also reduced TnTpSer208 in these cardiomyocytes, and PKCε-/- mice had lower TnTpSer208 levels than the wild-type. In parallel, HF increased TnT O-GlcNAcylation via both increased O-GlcNAc transferase and decreased O-GlcNAcase activity. Increasing O-GlcNAcylation (via O-GlcNAcase inhibition with Thiamet G) decreased TnTpSer208 in isolated hearts, while reducing O-GlcNAcylation (O-GlcNAc transferase siRNA) increased TnTpSer208 in neonatal cardiomyocytes. Mass spectrometry and NMR analysis identified O-GlcNAcylation of TnT on Ser190. CONCLUSION These data demonstrate interplay between Ser208 phosphorylation and Ser190 O-GlcNAcylation of TnT in ischaemic HF, linked to decreased activity of both PKCε and O-GlcNAcase and increased O-GlcNAc transferase activity. Modulation of these post-translational modifications of TnT may be a new therapeutic strategy in HF.
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Affiliation(s)
- Emilie Dubois-Deruy
- INSERM, U1167, 1 rue du Professeur Calmette, Lille, France Institut Pasteur de Lille, Lille, France University of Lille Nord de France, Lille, France
| | - Aude Belliard
- INSERM, U1167, 1 rue du Professeur Calmette, Lille, France Institut Pasteur de Lille, Lille, France University of Lille Nord de France, Lille, France
| | - Paul Mulder
- Inserm U1096, Rouen, France Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France
| | - Marion Bouvet
- INSERM, U1167, 1 rue du Professeur Calmette, Lille, France Institut Pasteur de Lille, Lille, France University of Lille Nord de France, Lille, France
| | - Caroline Smet-Nocca
- University of Lille Nord de France, Lille, France CNRS UMR 8576, Villeneuve D'Ascq, France
| | | | - Frank Lafont
- Institut Pasteur de Lille, Lille, France University of Lille Nord de France, Lille, France Bioimaging Center Lille Nord de France, Lille, France CNRS UMR 8204, INSERM U1019, Lille, France
| | - Olivia Beseme
- INSERM, U1167, 1 rue du Professeur Calmette, Lille, France Institut Pasteur de Lille, Lille, France University of Lille Nord de France, Lille, France
| | - Philippe Amouyel
- INSERM, U1167, 1 rue du Professeur Calmette, Lille, France Institut Pasteur de Lille, Lille, France University of Lille Nord de France, Lille, France Centre Hospitalier Régional et Universitaire de Lille, Lille, France
| | - Vincent Richard
- Inserm U1096, Rouen, France Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France
| | - Florence Pinet
- INSERM, U1167, 1 rue du Professeur Calmette, Lille, France Institut Pasteur de Lille, Lille, France University of Lille Nord de France, Lille, France
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Endothelin receptor blockade ameliorates renal injury by inhibition of RhoA/Rho-kinase signalling in deoxycorticosterone acetate-salt hypertensive rats. J Hypertens 2014; 32:795-805. [PMID: 24463935 DOI: 10.1097/hjh.0000000000000092] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW Excessive production of fibrosis is a feature of hypertension-induced renal injury. Activation of RhoA/Rho-kinase (ROCK) axis has been shown in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We assessed whether selective endothelin receptor blockers can attenuate renal fibrosis by inhibiting RhoA/ROCK axis in DOCA-salt rats. METHODS At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 4 weeks: vehicle, ABT-627 (endothelin-A receptor inhibitor) and A192621 (endothelin-B receptor inhibitor). RESULTS DOCA-salt was characterized by increased blood pressure, decreased renal function, increased proteinuria, increased glomerulosclerosis and tubulointerstitial fibrosis with myofibroblast accumulation, increased renal endothelin-1 levels and RhoA activity along with increased expression of connective tissue growth factor at both mRNA and protein levels as compared with uninephrectomized control male Wistar rats. Treatment with a selective mineralocorticoid receptor antagonist, eplerenone, ameliorated proteinuria. Impaired renal function and histological changes were overcome by treatment with ABT-627, but not with A192621. The beneficial effects of bosentan, a nonspecific endothelin receptor blocker, on proteinuria, RhoA activity, and connective tissue growth factor levels were similar to ABT-627. Furthermore, in an isolated perfuse kidney, a RhoA inhibitor, C3 exoenzyme, and two ROCK inhibitors, fasudil and Y-27632, significantly attenuated connective tissue growth factor levels. CONCLUSIONS These results indicate that DOCA-salt elevates renal endothelin-1 levels and RhoA activity via activation of mineralocorticoid receptor, resulting in renal fibrosis and proteinuria. Endothelin-A receptor blockade can attenuate DOCA-salt-induced renal fibrosis probably through the inhibition of RhoA/ROCK activity and connective tissue growth factor expression.
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Richard V. [Endothelin: From discovery to pharmacotherapeutic innovations]. Presse Med 2014; 43:742-55. [PMID: 24797866 DOI: 10.1016/j.lpm.2014.01.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 11/25/2013] [Accepted: 01/20/2014] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVES Endothelin (ET) is a major therapeutic target in cardiopulmonary diseases. The purpose of this review is to present the main concepts concerning ET biology, its pathophysiological roles and the major pharmacological and medical advances recently developed around the concept of ET receptor blockade. METHODS Analysis of PubMed database (keywords: endothelin, endothelin receptor antagonists, pulmonary hypertension, etc.), and of abstract originating from recent international meetings. RESULTS ET is a peptide produced by vascular endothelial cells as well as by many other tissues. Both its production and its effects are activated in pathological situations associated with endothelial dysfunction. ET is characterized by a strong tropism toward tissues because of its polarized release, the strong tissue receptor density and high affinity of the receptors for the peptide. ET exerts several vascular effects, including vasoconstriction, proliferation and hypertrophy, as well as non-vascular effects, notably stimulation of cardiac hypertrophy, tissue fibrosis and inflammation. Both vascular and non-vascular effects depend on the stimulation of two receptor subtypes, ETA and ETB. ET receptor antagonists (ERA) demonstrated beneficial effects in many different pre-clinical models of cardiovascular and pulmonary diseases, and constitute a first-line treatment of patients with pulmonary arterial hypertension (PAH). Recently, the targeted search for a novel ERA led to the development of macitentan which, compared to existing ERA, show optimized tissue penetration, increased receptor affinity and in vivo pharmacological efficacy in pre-clinical models, associated with a favorable profile, in terms of hepatic safety and drug interactions. The clinical efficacy of macitentan in the treatment of PAH was recently demonstrated in the SERAPHIN trial, which contrasts with previous PAH trials because of its long duration, the high number of patients enrolled, and its primary endpoint evaluating morbidity/mortality. Results show a significant reduction of the primary composite morbidity/mortality endpoint (taking into account both progression of PAH and death) by 30 and 45% with macitentan 3 and 10mg, respectively, compared to placebo, and confirm on the large scale the favorable tolerance profile, especially at the hepatic level. CONCLUSION The extensive knowledge on the complexity of the ET system allowed the synthesis of a new antagonist optimized, in terms of pharmacological efficacy and safety, which also show promising therapeutic effects in PAH patients, with demonstrated results in a prospective study using a composite primary endpoint of morbidity-mortality.
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Affiliation(s)
- Vincent Richard
- CHU de Rouen, service de pharmacologie, unité Inserm U1096, UFR médecine pharmacie de Rouen, 76183 Rouen cedex, France.
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Endothelin-1 and its role in the pathogenesis of infectious diseases. Life Sci 2014; 118:110-9. [PMID: 24780317 DOI: 10.1016/j.lfs.2014.04.021] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 04/08/2014] [Accepted: 04/15/2014] [Indexed: 12/12/2022]
Abstract
Endothelins are potent regulators of vascular tone, which also have mitogenic, apoptotic, and immunomodulatory properties (Rubanyi and Polokoff, 1994; Kedzierski and Yanagisawa, 2001; Bagnato et al., 2011). Three isoforms of endothelin have been identified to date, with endothelin-1 (ET-1) being the best studied. ET-1 is classically considered a potent vasoconstrictor. However, in addition to the effects of ET-1 on vascular smooth muscle cells, the peptide is increasingly recognized as a pro-inflammatory cytokine (Teder and Noble, 2000; Sessa et al., 1991). ET-1 causes platelet aggregation and plays a role in the increased expression of leukocyte adhesion molecules, the synthesis of inflammatory mediators contributing to vascular dysfunction. High levels of ET-1 are found in alveolar macrophages, leukocytes (Sessa et al., 1991) and fibroblasts (Gu et al., 1991). Clinical and experimental data indicate that ET-1 is involved in the pathogenesis of sepsis (Tschaikowsky et al., 2000; Goto et al., 2012), viral and bacterial pneumonia (Schuetz et al., 2008; Samransamruajkit et al., 2002), Rickettsia conorii infections (Davi et al., 1995), Chagas disease (Petkova et al., 2000, 2001), and severe malaria (Dai et al., 2012; Machado et al., 2006; Wenisch et al., 1996a; Dietmann et al., 2008). In this minireview, we will discuss the role of endothelin in the pathogenesis of infectious processes.
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