| First Author | Sadayappan S | Year | 2009 |
| Journal | Circulation | Volume | 119 |
| Issue | 9 | Pages | 1253-62 |
| PubMed ID | 19237661 | Mgi Jnum | J:166006 |
| Mgi Id | MGI:4839435 | Doi | 10.1161/CIRCULATIONAHA.108.798983 |
| Citation | Sadayappan S, et al. (2009) Cardiac myosin binding protein-C phosphorylation in a {beta}-myosin heavy chain background. Circulation 119(9):1253-62 |
| abstractText | 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-C(AllP+)) 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-C(AllP)(-)), or cMyBP-C(AllP+) 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-C(AllP)(-)(:(t/t)/beta) mice died prematurely because of heart failure, confirming that cMyBP-C phosphorylation is essential in the beta-MyHC background. cMyBP-C(AllP+:(t/t)/beta) and cMyBP-C(WT:(t/t)/beta) hearts showed no morbidity and mortality, and cMyBP-C(AllP+:(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. |
