Targeting calpain-2-mediated junctophilin-2 cleavage delays heart failure progression following myocardial infarction.

Autor: Lahiri SK; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Lu J; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA; Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine., Aguilar-Sanchez Y; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Li H; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Moreira LM; Cardiovascular Medicine, Radcliffe Dept of Medicine, University of Oxford, UK., Hulsurkar MM; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Mendoza A; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Turkieltaub Paredes MR; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Navarro-Garcia JA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Munivez E; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Horist B; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Moore OM; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Weninger G; Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA., Brandenburg S; Department of Cardiology & Pneumology, Heart Research Center Göttingen; Cellular Biophysics and Translational Cardiology Section, University Medical Center Göttingen, Göttingen, Germany., Lenz C; Department of Clinical Chemistry, University Medical Center Göttingen, Germany; Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany., Lehnart SE; Department of Cardiology & Pneumology, Heart Research Center Göttingen; Cellular Biophysics and Translational Cardiology Section, University Medical Center Göttingen, Göttingen, Germany., Sayeed R; Cardiothoracic Unit, John Radcliffe Hospital, Oxford, UK., Krasopoulos G; Cardiothoracic Unit, John Radcliffe Hospital, Oxford, UK., Srivastava V; Cardiothoracic Unit, John Radcliffe Hospital, Oxford, UK., Zhang L; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Karch JM; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Reilly S; Cardiovascular Medicine, Radcliffe Dept of Medicine, University of Oxford, UK., Wehrens XHT; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA; Department of Medicine/Cardiology, Baylor College of Medicine, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Center for Space Medicine, Baylor College of Medicine, Houston, TX, USA. Electronic address: wehrens@bcm.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2024 Sep; Vol. 194, pp. 85-95. Date of Electronic Publication: 2024 Jul 02.
DOI: 10.1016/j.yjmcc.2024.06.011
Abstrakt: Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia of the cardiac muscle, which results in myocardial infarction (MI). Junctophilin-2 (JPH2) is a membrane protein that ensures efficient calcium handling and proper excitation-contraction coupling. Studies have identified loss of JPH2 due to calpain-mediated proteolysis as a key pathogenic event in ischemia-induced heart failure (HF). Our findings show that calpain-2-mediated JPH2 cleavage yields increased levels of a C-terminal cleaved peptide (JPH2-CTP) in patients with ischemic cardiomyopathy and mice with experimental MI. We created a novel knock-in mouse model by removing residues 479-SPAGTPPQ-486 to prevent calpain-2-mediated cleavage at this site. Functional and molecular assessment of cardiac function post-MI in cleavage site deletion (CSD) mice showed preserved cardiac contractility and reduced dilation, reduced JPH2-CTP levels, attenuated adverse remodeling, improved T-tubular structure, and normalized SR Ca 2+ -handling. Adenovirus mediated calpain-2 knockdown in mice exhibited similar findings. Pulldown of CTP followed by proteomic analysis revealed valosin-containing protein (VCP) and BAG family molecular chaperone regulator 3 (BAG3) as novel binding partners of JPH2. Together, our findings suggest that blocking calpain-2-mediated JPH2 cleavage may be a promising new strategy for delaying the development of HF following MI.
Competing Interests: Declaration of competing interest XHTW is a consultant for Pfizer and Rocket Pharmaceuticals, and a founding partner and board member of Elex Biotech Inc., a start-up company that developed drug molecules that target ryanodine receptors to treat cardiac arrhythmia disorders. LZ is the co-founder and consultant for Pelagos Pharma Inc., a start-up company that develop drug molecules that target nuclear receptors to treat heart failure and neurodegenerative disorders. Other authors have no potential conflicts to disclose. AI-assisted technology is not used in the preparation of this work (except checking grammar and spelling).
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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