PKC-α regulates cardiac contractility and propensity toward heart failure

Julian C. Braz, Kimberly Gregory, Anand Pathak, Wen Zhao, Bogachan Sahin, Raisa Klevitsky, Thomas F. Kimball, John N. Lorenz, Angus C. Nairn, Stephen B. Liggett, Ilona Bodi, Su Wang, Arnold Schwartz, Edward G. Lakatta, Anna A. DePaoli-Roach, Jeffrey Robbins, Timothy E. Hewett, James A. Bibb, Margaret V. Westfall, Evangelia G. KraniasJeffery D. Molkentin

Research output: Contribution to journalArticle

451 Scopus citations

Abstract

The protein kinase C (PKC) family of serine/threonine kinases functions downstream of nearly all membrane-associated signal transduction pathways. Here we identify PKC-α as a fundamental regulator of cardiac contractility and Ca2+ handling in myocytes. Hearts of Prkca-deficient mice are hypercontractile, whereas those of transgenic mice overexpressing Prkca are hypocontractile. Adenoviral gene transfer of dominant-negative or wild-type PKC-α into cardiac myocytes enhances or reduces contractility, respectively. Mechanistically, modulation of PKC-α activity affects dephosphorylation of the sarcoplasmic reticulum Ca2+ ATPase-2 (SERCA-2) pump inhibitory protein phospholamban (PLB), and alters sarcoplasmic reticulum Ca2+ loading and the Ca2+ transient. PKC-α directly phosphorylates protein phosphatase inhibitor-1 (I-1), altering the activity of protein phosphatase-1 (PP-1), which may account for the effects of PKC-α on PLB phosphorylation. Hypercontractility caused by Prkca deletion protects against heart failure induced by pressure overload, and against dilated cardiomyopathy induced by deleting the gene encoding muscle LIM protein (Csrp3). Deletion of Prkca also rescues cardiomyopathy associated with overexpression of PP-1. Thus, PKC-α functions as a nodal integrator of cardiac contractility by sensing intracellular Ca2+ and signal transduction events, which can profoundly affect propensity toward heart failure.

Original languageEnglish (US)
Pages (from-to)248-254
Number of pages7
JournalNature Medicine
Volume10
Issue number3
DOIs
StatePublished - Mar 1 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Braz, J. C., Gregory, K., Pathak, A., Zhao, W., Sahin, B., Klevitsky, R., Kimball, T. F., Lorenz, J. N., Nairn, A. C., Liggett, S. B., Bodi, I., Wang, S., Schwartz, A., Lakatta, E. G., DePaoli-Roach, A. A., Robbins, J., Hewett, T. E., Bibb, J. A., Westfall, M. V., ... Molkentin, J. D. (2004). PKC-α regulates cardiac contractility and propensity toward heart failure. Nature Medicine, 10(3), 248-254. https://doi.org/10.1038/nm1000