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(Circulation. 2006;114:574-582.)
© 2006 American Heart Association, Inc.

Heart Failure

Pharmacological- and Gene Therapy-Based Inhibition of Protein Kinase C/ß Enhances Cardiac Contractility and Attenuates Heart Failure

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

From the Department of Pediatrics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center (M.H., R.K., T.F.K., T.E.H., J.D.M.) and the Departments of Molecular Genetics (M.H.) and Medicine, University of Cincinnati (H.H., G.W.D.), Cincinnati, Ohio; Procter and Gamble Pharmaceuticals (A.N.C), Cincinnati, Ohio; and the Center for Translational Medicine, Jefferson Medical College (S.T.P., M.C.K., W.J.K), Philadelphia, Pa.

Correspondence to Jeffery D. Molkentin, PhD, Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.molkentin{at}cchmc.org

Received September 30, 2005; revision received May 18, 2006; accepted June 12, 2006.

Background— The conventional protein kinase C (PKC) isoform functions as a proximal regulator of Ca²⁺ handling in cardiac myocytes. Deletion of PKC in the mouse results in augmented sarcoplasmic reticulum Ca²⁺ loading, enhanced Ca²⁺ transients, and augmented contractility, whereas overexpression of PKC in the heart blunts contractility. Mechanistically, PKC directly regulates Ca²⁺ 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 Ca²⁺ 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 PKC-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 PKC cDNA rescued heart failure in a rat model of postinfarction cardiomyopathy. PKC 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 PKC, or the conventional isoforms in general, may serve as a novel therapeutic strategy for enhancing cardiac contractility in certain stages of heart failure.

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