Dissociation of Structural and Functional Phenotypes in Cardiac Myosin Binding Protein-C Conditional Knock-Out Mice
Background—Cardiac myosin binding protein-C (cMyBP-C) is a sarcomeric protein that dynamically regulates thick filament structure and function. In constitutive cMyBP-C knock-out (cMyBP-C-/-) mice, loss of cMyBP-C has been linked to left ventricular (LV) dilation, cardiac hypertrophy, and systolic and diastolic dysfunction, although the pathogenesis of these phenotypes remains unclear.
Methods and Results—We generated cMyBP-C conditional knock-out (cMyBP-C-cKO) mice expressing floxed cMyBP-C alleles and a tamoxifen-inducible Cre-recombinase fused to two mutated estrogen receptors to study the onset and progression of structural and functional phenotypes due to the loss of cMyBP-C. In adult cMyBP-C-cKO mice, knock-down 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 knock-down of cMyBP-C. In response to pressure overload induced by transaortic constriction, cMyBP-C-cKO mice treated with tamoxifen also developed greater cardiac hypertrophy, LV dilation, and reduced contractile function.
Conclusions—These results indicate that myocardial dysfunction is largely due to the removal of cMyBP-C and occurs prior to 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, highlighting the importance of additional factors such as loading stress in determining the expression and progression of cMyBP-C-associated cardiomyopathy.
- Received December 21, 2011.
- Accepted July 13, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited