Phospholamban ablation normalized cardiomyocyte contractility in vitro but failed to improve in vivo global cardiac function or prevent ventricular failure in genetic mouse models of hypertrophy.
Does phospholamban ablation improve in vivo cardiac function and hypertrophy in genetic mouse models of hypertrophy and cardiac failure?
Phospholamban ablation improves isolated myocyte contractility but fails to rescue the in vivo cardiomyopathic phenotype in genetic models of hypertrophy.
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.
Song et al. (Sat,) conducted a other in Genetic cardiac hypertrophy and failure. Phospholamban (PLN) ablation vs. Wild-type and single transgenic (Gαq or MyBP-CMUT) mice was evaluated on In vivo global cardiac function (fractional shortening and left ventricular end diastolic dimension). Phospholamban ablation normalized cardiomyocyte contractility in vitro but failed to improve in vivo global cardiac function or prevent ventricular failure in genetic mouse models of hypertrophy.
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