Dissociation of Structural and Functional Phenotypes in Cardiac Myosin-Binding Protein C Conditional Knockout Mice

Article

关键词: FAMILIAL HYPERTROPHIC CARDIOMYOPATHY;    ASYMMETRIC SEPTAL HYPERTROPHY;    DILATED CARDIOMYOPATHY;    MISSENSE MUTATION;    MYBPC3 GENE;    NULL MICE;    PHOSPHORYLATION;    HAPLOINSUFFICIENCY;    DYSFUNCTION;    MYOCARDIUM;   

DOI  :  10.1161/CIRCULATIONAHA.111.089219

来源: SCIE

【 摘 要 】

Background-Cardiac myosin-binding protein C (cMyBP-C) is a sarcomeric protein that dynamically regulates thick-filament structure and function. In constitutive cMyBP-C knockout (cMyBP-C (-/-)) mice, loss of cMyBP-C has been linked to left ventricular dilation, cardiac hypertrophy, and systolic and diastolic dysfunction, although the pathogenesis of these phenotypes remains unclear. Methods and Results-We generated cMyBP-C conditional knockout (cMyBP-C-cKO) mice expressing floxed cMyBP-C alleles and a tamoxifen-inducible Cre-recombinase fused to 2 mutated estrogen receptors to study the onset and progression of structural and functional phenotypes caused by the loss of cMyBP-C. In adult cMyBP-C-cKO mice, knockdown of cMyBP-C over a 2-month period resulted in a corresponding impairment of diastolic function and a concomitant abbreviation of systolic ejection, although contractile function was largely preserved. No significant changes in cardiac structure or morphology were immediately evident; however, mild hypertrophy developed after near-complete knockdown of cMyBP-C. In response to pressure overload induced by transaortic constriction, cMyBP-C-cKO mice treated with tamoxifen also developed greater cardiac hypertrophy, left ventricular dilation, and reduced contractile function. Conclusions-These results indicate that myocardial dysfunction is largely caused by the removal of cMyBP-C and occurs before the onset of cytoarchitectural remodeling in tamoxifen-treated cMyBP-C-cKO myocardium. Moreover, near ablation of cMyBP-C in adult myocardium primarily leads to the development of hypertrophic cardiomyopathy in contrast to the dilated phenotype evident in cMyBP-C (-/-) mice, which highlights the importance of additional factors such as loading stress in determining the expression and progression of cMyBP-C-associated cardiomyopathy. (Circulation. 2012;126:1194-1205.)

【 授权许可】

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