Pharmacological- and gene therapy-based inhibition of protein kinase Cα/β enhances cardiac contractility and attenuates heart failure

Michael Hambleton, Harvey Hahn, Sven T. Pleger, Matthew C. Kuhn, Raisa Klevitsky, Andrew N. Carr, Thomas F. Kimball, Timothy E. Hewett, Gerald W. Dorn, Walter J. Koch, Jeffery D. Molkentin

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

BACKGROUND - The conventional protein kinase C (PKC) isoform α functions as a proximal regulator of Ca handling in cardiac myocytes. Deletion of PKCα in the mouse results in augmented sarcoplasmic reticulum Ca loading, enhanced Ca transients, and augmented contractility, whereas overexpression of PKCα in the heart blunts contractility. Mechanistically, PKCα directly regulates Ca handling by altering the phosphorylation status of inhibitor-1, which in turn suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and secondarily, the sarcoplasmic reticulum Ca ATPase. METHODS AND RESULTS - In the present study, we show that short-term inhibition of the conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work-performing heart preparation in wild-type mice but not in PKCα-deficient mice. Ro-32-0432 also increased cardiac contractility in 2 different models of heart failure in vivo. Short-term or long-term treatment with Ro-31-8220 in a mouse model of heart failure due to deletion of the muscle lim protein gene significantly augmented cardiac contractility and restored pump function. Moreover, adenovirus-mediated gene therapy with a dominant-negative PKCα cDNA rescued heart failure in a rat model of postinfarction cardiomyopathy. PKCα was also determined to be the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology. CONCLUSIONS - Pharmacological inhibition of PKCα, or the conventional isoforms in general, may serve as a novel therapeutic strategy for enhancing cardiac contractility in certain stages of heart failure.

Original languageEnglish (US)
Pages (from-to)574-582
Number of pages9
JournalCirculation
Volume114
Issue number6
DOIs
StatePublished - Aug 1 2006

Keywords

  • Cardiomyopathy
  • Contractility
  • Heart failure
  • Protein kinase C

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Hambleton, M., Hahn, H., Pleger, S. T., Kuhn, M. C., Klevitsky, R., Carr, A. N., Kimball, T. F., Hewett, T. E., Dorn, G. W., Koch, W. J., & Molkentin, J. D. (2006). Pharmacological- and gene therapy-based inhibition of protein kinase Cα/β enhances cardiac contractility and attenuates heart failure. Circulation, 114(6), 574-582. https://doi.org/10.1161/CIRCULATIONAHA.105.592550