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

Qiujing Song, Albrecht G. Schmidt, Harvey S. Hahn, Andrew N. Carr, Beate Frank, Luke Pater, Mike Gerst, Karen Young, Brian D. Hoit, Bradley K. McConnell, Kobra Haghighi, Christine E. Seidman, Jonathan G. Seidman, Gerald W. Dorn, Evangelia G. Kranias

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca2+ cycling. Normalization of Ca2+ 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-CMUT) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca2+ transients and enhanced unloaded fractional shortening with no change in SR Ca2+ 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.

Original languageEnglish
Pages (from-to)859-867
Number of pages9
JournalJournal of Clinical Investigation
Volume111
Issue number6
DOIs
StatePublished - Mar 1 2003
Externally publishedYes

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    Song, Q., Schmidt, A. G., Hahn, H. S., Carr, A. N., Frank, B., Pater, L., Gerst, M., Young, K., Hoit, B. D., McConnell, B. K., Haghighi, K., Seidman, C. E., Seidman, J. G., Dorn, G. W., & Kranias, E. G. (2003). Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy. Journal of Clinical Investigation, 111(6), 859-867. https://doi.org/10.1172/JCI200316738