Background— The conventional protein kinase C (PKC) isoform α functions as a proximal regulator of Ca²⁺ handling in cardiac myocytes. Deletion of PKCα in the mouse results in augmented sarcoplasmic reticulum Ca²⁺ loading, enhanced Ca²⁺ transients, and augmented contractility, whereas overexpression of PKCα in the heart blunts contractility. Mechanistically, PKCα 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 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.