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

Abstract

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, Galphaq 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 Galphaq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Galphaq pathway or MyBP-C mutations.

Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats

“…No effect of PLN ablation on echocardiographic measures of hypertrophy and dysfunction were observed in either model, and impaired hemodynamic responsiveness to β-adrenergic stimulation was not affected (14). These findings contrast with those of our previous study on PLN ablation in MLP cardiomyopathic mice (using a similar crossbreeding approach), in which the cardiomyopathic phenotype did not develop (12), and they also differ from the present findings in the adult rat with MI, in which an entirely different approach was used to achieve PLN inhibition in the presence of established cardiac dysfunction and dilation.…”

“…In a recent report, the effects of PLN ablation, produced by crossbreeding with PLN-null mice, were assessed in two genetic mouse models, Gαq overexpression and targeted mutation of myosin-binding protein C, both of which exhibited extensive cardiomyopathic changes associated with the development of cardiac dysfunction and dilation (14). No effect of PLN ablation on echocardiographic measures of hypertrophy and dysfunction were observed in either model, and impaired hemodynamic responsiveness to β-adrenergic stimulation was not affected (14).…”

“…It seems possible that in the two transgenic models described above (14), the strong genetic stimuli mediating cardiomyopathic changes, present in utero and thereafter, may have overshadowed the effect of PLN ablation to enhance cardiomyocyte contractility. In the MLP cardiomyopathic model, on the other hand, cardiac dilation and hypertrophy develop progressively over several weeks after birth (45,46), and in that setting, correction by PLN ablation of the Ca 2+ handling defect during postnatal cardiac growth may explain the observed complete prevention of the dilated cardiomyopathy phenotype (12).…”

“…In one study, apoptotic heart failure resulted from overexpression of a signaling molecule, or severe neonatal-onset cardiac dilation was induced by targeted mutation of a structural protein, and neither was modified by PLN ablation (14). Also, Kiriazis et al have reported that hyperdynamic PLN-null mice do not differ from wild-type mice in the development of hypertrophy or in the incidence of heart failure after sustained surgical aortic stenosis (15).…”

Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human

“…To our knowledge, this is the first instance of a human equivalent of the PLN-null mouse. The apparent pathological effects of absent PLN in human hearts contrast strikingly with benefits observed in many, although not all (39), mouse heart failure models. These data emphasize a general concern that targeted therapies whose design is based exclusively on results of studies in rodent models, in which phenotypes can differ radically from those observed in the corresponding human genetic condition, may not ultimately be successful in human disease.…”