Cardiac Myosin Binding Protein-C Phosphorylation in a beta-Myosin Heavy Chain Background

Article

关键词: FAMILIAL HYPERTROPHIC CARDIOMYOPATHY;    ACTOMYOSIN ATPASE ACTIVITY;    KINASE-A PHOSPHORYLATION;    TROPONIN-I;    STRETCH ACTIVATION;    REGULATORY DOMAIN;    HEART-FAILURE;    SITE MUTATION;    RAT-HEART;    MYBP-C;   

DOI  :  10.1161/CIRCULATIONAHA.108.798983

来源: SCIE

【 摘 要 】

Background-Cardiac myosin binding protein-C (cMyBP-C) phosphorylation modulates cardiac contractility. When expressed in cMyBP-C-null (cMyBP-C-(t/t)) hearts, a cMyBP-C phosphomimetic (cMyBP-CAllP+) rescued cardiac dysfunction and protected the hearts from ischemia/reperfusion injury. However, cMyBP-C function may be dependent on the myosin isoform type. Because these replacements were performed in the mouse heart, which contains predominantly alpha-myosin heavy chain (alpha-MyHC), the applicability of the data to humans, whose cardiomyocytes contain predominantly beta-MyHC, is unclear. We determined the effect(s) of cMyBP-C phosphorylation in a beta-MyHC transgenic mouse heart in which >80% of the alpha-MyHC was replaced by beta-MyHC, which is the predominant myosin isoform in human cardiac muscle. Methods and Results-To determine the effects of cMyBP-C phosphorylation in a beta-MyHC background, transgenic mice expressing normal cMyBP-C (cMyBP-C-WT), nonphosphorylatable cMyBP-C (cMyBP-CAllP-), or cMyBP-CAllP+ were bred into the beta-MyHC background (beta). These mice were then crossed into the cMyBP-C(t/t) background to ensure the absence of endogenous cMyBP-C. cMyBP-C-(t/t)/beta and cMyBP-CAllP-:(t/t)/beta mice died prematurely because of heart failure, confirming that cMyBP-C phosphorylation is essential in the beta-MyHC background. cMyBP-CAllP+:(t/t)/beta and cMyBP-C-WT:(t/t)/beta hearts showed no morbidity and mortality, and cMyBP-CAllP+:(t/t)/beta hearts were significantly cardioprotected from ischemia/reperfusion injury. Conclusions-cMyBP-C phosphorylation is necessary for basal myocardial function in the beta-MyHC background and can preserve function after ischemia/reperfusion injury. Our studies justify exploration of cMyBP-C phosphorylation as a therapeutic target in the human heart. (Circulation. 2009; 119: 1253-1262.)

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