Targeting calpain-2-mediated junctophilin-2 cleavage delays heart failure progression following myocardial infarction.
J Mol Cell Cardiol
; 194: 85-95, 2024 Sep.
Article
em En
| MEDLINE
| ID: mdl-38960317
ABSTRACT
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 Ca2+-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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Calpaína
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Insuficiência Cardíaca
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Proteínas de Membrana
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Infarto do Miocárdio
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Mol Cell Cardiol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos