| First Author | Chen PP | Year | 2012 |
| Journal | Circulation | Volume | 126 |
| Issue | 10 | Pages | 1194-205 |
| PubMed ID | 22829020 | Mgi Jnum | J:202199 |
| Mgi Id | MGI:5517647 | Doi | 10.1161/CIRCULATIONAHA.111.089219 |
| Citation | Chen PP, et al. (2012) Dissociation of structural and functional phenotypes in cardiac myosin-binding protein C conditional knockout mice. Circulation 126(10):1194-205 |
| abstractText | 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. |
