Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy

Abstract

IntroductionIn the face of unremitting hemodynamic stress, "adaptive" cardiac hypertrophy inevitably progresses to ventricular dilation and clinical heart failure, which affects an estimated 5 million Americans and has a mortality rate of approximately 50% in 4 years (1). A nearly universal characteristic of hypertrophied and failing myocardium is depressed sarcoplasmic reticulum (SR) Ca 2+ cycling, caused by decreased expression of the cardiac SR Ca 2+ ATPase (SERCA2a), by a relative overabundance of the SERCA2a inhibitory protein phospholamban (PLN), or by both (2, 3). Recent experimental successes have generated enthusiasm for treating heart failure by restoring SR Ca 2+ cycling, either through adenoviral-mediated myocardial-targeted expression of SERCA2a itself (4) or through antisense suppression (5) or genetic ablation of PLN (6), to relieve SERCA2a from endogenous inhibition. The common result of each approach is enhanced SR Ca 2+ cycling, which has improved energetics, survival, and cardiac function at the cellular, organ, and intact animal levels. Furthermore, there is no compromise in exercise performance or longevity in the case of PLN ablation (7,8).To date, PLN ablation or inhibition has improved SR Ca 2+ cycling and/or contractile function in transgenic Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca 2+ cycling. Normalization of Ca 2+ cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Gαq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C MUT ) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca 2+ transients and enhanced unloaded fractional shortening with no change in SR Ca 2+ pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Gαq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Gαq pathway or MyBP-C mutations.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Kinetics of cardiac muscle contraction and relaxation are linked and determined by properties of the cardiac sarcomere

“…Thus, although there are conditions in which the contraction and relaxation kinetic balance is disrupted, these only occur under very nonphysiological conditions. Moreover, in the MyBP-C truncated strain, where Ca 2ϩ transients display a delayed Ca 2ϩ uptake, normalizing the uptake in isolated myocytes by crossing this strain with phospholamban knockout mice normalized contraction and relaxation, but only in unloaded myocytes at low pacing rates; the ventricular function remained impaired (34). Thus, under all but extremely nonphysiological experimental conditions, contraction-relaxation coupling is constant and not changed by processes that generally govern cardiac output.…”

Excitation-contraction coupling and mitochondrial energetics

“…13) without activating receptor-mediated pathways (e. g., β-adrenergic receptors) could be promising. In experimental heart failure models, transgenic inhibition or deletion of phospholamban [51, 116,134] or adenoviral increase of SR Ca 2+ -ATPase expression [52] frequently, but not always [185], improved LV function and survival. Interestingly, the increase of SR Ca 2+ -ATPase expression was associated with an improvement of the PCr/ATP ratio in rats with heart failure after aortic banding [52], supporting the hypothesis that reconstitution of EC coupling may improve energetics.…”

Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58

“…All measurements and calculations were done in triplicate. Percent fractional shortening, ejection fraction, and LV mass were calculated as previously described (28).…”