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PKC-α regulates cardiac contractility and propensity toward heart failure

Nature Medicine volume 10, pages 248–254 (2004)Cite this article

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.

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Figure 1: Generation and characterization of Prkca gene–targeted mice.
Figure 2: Transgenic mice expressing PKC-α have reduced ventricular performance.
Figure 3: Changes in PKC-α activity correlate with PLB phosphorylation status and Ca2+ handling.
Figure 4: Loss of Prkca prevents cardiomyopathy in two distinct models of heart failure.
Figure 5: PKC-α regulates PP-1 activity through I-1.
Figure 6: Loss of Prkca rescues cardiomyopathy in mice overexpressing PP-1c.

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Acknowledgements

This work was supported by the National Institutes of Health, an Established Investigator Award from the American Heart Association, and a Pew Charitable Trust Scholar Award (J.D.M.). J.C.B. was supported by a National Institutes of Health training grant (5T32 HL07382). J.A.B. was supported by the National Institute of Drug Abuse. We thank T. Eschenhagen for the I-1-expressing adenovirus and S. Schenolikar for antibodies to I-1 and Thr35-phoshorylated I-1.

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Authors and Affiliations

  1. Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, Cincinnati, 45229-3039, Ohio, USA

    Julian C Braz, Raisa Klevitsky, Thomas F Kimball, Jeffrey Robbins, Timothy E Hewett & Jeffery D Molkentin

  2. Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, 45267, Ohio, USA

    Julian C Braz, Kimberly Gregory, Anand Pathak, Wen Zhao, Stephen B Liggett & Evangelia G Kranias

  3. Department of Psychiatry, University of Texas Southwestern, Dallas, 75390, Texas, USA

    Bogachan Sahin & James A Bibb

  4. Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, 45267, Ohio, USA

    John N Lorenz

  5. Department of Psychiatry, Yale University School of Medicine, New Haven, 06508, Connecticut, USA

    Angus C Nairn

  6. Institute of Molecular Pharmacology and Biophysics, University of Cincinnati, Cincinnati, 45267, Ohio, USA

    Ilona Bodi & Arnold Schwartz

  7. National Institutes on Aging, Laboratory of Cardiovascular Science, Baltimore, 21224, Maryland, USA

    Su Wang & Edward G Lakatta

  8. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA

    Anna A DePaoli-Roach

  9. Section of Cardiac Surgery, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Margaret V Westfall

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Correspondence to Jeffery D Molkentin.

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Braz, J., Gregory, K., Pathak, A. et al. PKC-α regulates cardiac contractility and propensity toward heart failure. Nat Med 10, 248–254 (2004). https://doi.org/10.1038/nm1000

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