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J Mol Cell Cardiol. 2019 Mar 9;129:236-246. doi: 10.1016/j.yjmcc.2019.03.006. [Epub ahead of print]

Ablation of the calpain-targeted site in cardiac myosin binding protein-C is cardioprotective during ischemia-reperfusion injury.

Author information

1
Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, USA; Center for Genetic Medicine, Northwestern University, Chicago, IL, USA. Electronic address: david.barefield@northwestern.edu.
2
Heart, Lung and Vascular Institute, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
3
Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, USA; Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, USA.
4
Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, USA; Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, the Netherlands.
5
Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, USA.
6
Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, USA.
7
Department of Physiology and Biophysics, Boston University, Boston, MA, USA.
8
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
9
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
10
Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, UK.
11
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary.
12
Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.
13
Department of Physiology and Biophysics, Rush University, Chicago, IL, USA.
14
Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, OH, USA.
15
Research Service, Providence VA Medical Center and Brown University, Providence, RI, USA.
16
Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, USA; Heart, Lung and Vascular Institute, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA. Electronic address: sadayasl@ucmail.uc.edu.

Abstract

Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is essential for normal heart function and protects the heart from ischemia-reperfusion (I/R) injury. It is known that protein kinase-A (PKA)-mediated phosphorylation of cMyBP-C prevents I/R-dependent proteolysis, whereas dephosphorylation of cMyBP-C at PKA sites correlates with its degradation. While sites on cMyBP-C associated with phosphorylation and proteolysis co-localize, the mechanisms that link cMyBP-C phosphorylation and proteolysis during cardioprotection are not well understood. Therefore, we aimed to determine if abrogation of cMyBP-C proteolysis in association with calpain, a calcium-activated protease, confers cardioprotection during I/R injury. Calpain is activated in both human ischemic heart samples and ischemic mouse myocardium where cMyBP-C is dephosphorylated and undergoes proteolysis. Moreover, cMyBP-C is a substrate for calpain proteolysis and cleaved by calpain at residues 272-TSLAGAGRR-280, a domain termed as the calpain-target site (CTS). Cardiac-specific transgenic (Tg) mice in which the CTS motif was ablated were bred into a cMyBP-C null background. These Tg mice were conclusively shown to possess a normal basal structure and function by analysis of histology, electron microscopy, immunofluorescence microscopy, Q-space MRI of tissue architecture, echocardiography, and hemodynamics. However, the genetic ablation of the CTS motif conferred resistance to calpain-mediated proteolysis of cMyBP-C. Following I/R injury, the loss of the CTS reduced infarct size compared to non-transgenic controls. Collectively, these findings demonstrate the physiological significance of calpain-targeted cMyBP-C proteolysis and provide a rationale for studying inhibition of calpain-mediated proteolysis of cMyBP-C as a therapeutic target for cardioprotection.

KEYWORDS:

Calpain; Cardioprotection; Ischemia-reperfusion injury; MYBPC3; cMyBP-C

PMID:
30862451
DOI:
10.1016/j.yjmcc.2019.03.006
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