@article{0e3e039d472e4acfb467c638dedc271a,
title = "Ablation of the calpain-targeted site in cardiac myosin binding protein-C is cardioprotective during ischemia-reperfusion injury",
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",
author = "Barefield, {David Y.} and McNamara, {James W.} and Lynch, {Thomas L.} and Kuster, {Diederik W.D.} and Suresh Govindan and Lauren Haar and Yang Wang and Taylor, {Erik N.} and Lorenz, {John N.} and Nieman, {Michelle L.} and Guangshuo Zhu and Luther, {Pradeep K.} and Andras Varr{\'o} and Dobromir Dobrev and Xun Ai and Janssen, {Paul M.L.} and Kass, {David A.} and Jones, {Walter Keith} and Gilbert, {Richard J.} and Sakthivel Sadayappan",
note = "Funding Information: The authors were supported by NIH National Heart, Lung, and Blood grants, including R01HL130356, R01HL105826, and K02HL114749 (to S.S.); R01DC011528 (to R.J.G.); and F32HL131304 (to D.Y.B), R01-HL131517 and R01-HL136389 (to D.D.), the American Heart Association Midwest Affiliate Research Programs, including Cardiovascular Genome-Phenome Study 15CVGPSD27020012 and Catalyst 17CCRG33671128 (to S.S.), Predoctoral Fellowship 11PRE7240022 (to D.Y.B.), Postdoctoral Fellowship 13POST14720024 (to S.G.), Postdoctoral Fellowship 13POST17220009 (to D.W.D.K.), Predoctoral Fellowship 15PRE22430028 (to T.L.L.IV.), Postdoctoral Fellowship 17POST33630095 (to J.W.M), and a British Heart Foundation Programme Grant RG/11/21/29335 (to P.K.L.). Funding Information: The authors were supported by NIH National Heart, Lung, and Blood grants, including R01HL130356 , R01HL105826 , and K02HL114749 (to S.S.); R01DC011528 (to R.J.G.); and F32HL131304 (to D.Y.B), R01-HL131517 and R01-HL136389 (to D.D.), the American Heart Association Midwest Affiliate Research Programs , including Cardiovascular Genome-Phenome Study 15CVGPSD27020012 and Catalyst 17CCRG33671128 (to S.S.), Predoctoral Fellowship 11PRE7240022 (to D.Y.B.), Postdoctoral Fellowship 13POST14720024 (to S.G.), Postdoctoral Fellowship 13POST17220009 (to D.W.D.K.), Predoctoral Fellowship 15PRE22430028 (to T.L.L.IV.), Postdoctoral Fellowship 17POST33630095 (to J.W.M), and a British Heart Foundation Programme Grant RG/11/21/29335 (to P.K.L.). Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = apr,
doi = "10.1016/j.yjmcc.2019.03.006",
language = "English (US)",
volume = "129",
pages = "236--246",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",
}