2008 Thomas W. Smith Memorial Lecture—Protein Kinase C α as a Novel Therapeutic Target for Treating Heart Failure
We have shown that protein kinase C (PKC) α functions as a proximal regulator of Ca2+ handling in cardiac myocytes (Braz et al, Nat. Med. 10:248, 2004). Deletion of PKCα in the mouse resulted in augmented sarcoplasmic reticulum Ca2+ loading, enhanced Ca2+ transients, and augmented contractility, whereas overexpression of PKCα in the heart blunted contractility. Mechanistically, PKCα regulates Ca2+ handling by altering inhibitor-1 phosphorylation, which suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and sarcoplasmic reticulum Ca2+ AT-Pase 2 (SERCA2). Acute inhibition of PKCα with the pharmacologic agents 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 acutely increased cardiac contractility in two different models of heart failure in vivo. Moreover, acute or chronic treatment with Ro-32-8220 in a mouse model of heart failure, due to deletion of the muscle lim protein (MLP) gene, significantly augmented cardiac contractility and restored normal pump function. Adenoviral-mediated gene therapy with a dominant negative PKCα cDNA rescued heart failure in a chronic rat model of postinfarction cardiomyopathy. Moreover, expression of dominant-negative PKCα in cardiac myocytes using a cardiac-specific transgenic system (tetracycline-regulated) also enhanced cardiac contractility and antagonized heart failure due to myocardial infarction injury. Finally, another PKCα/β inhibitor, ruboxistaurin (LY333531), antagonized heart failure after long-term pressure overload in mice. PKCα is the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology. Indeed, pharmacological inhibition of PKCα may serve as a novel therapeutic strategy for either enhancing cardiac contractility in the setting of severe functional deterioration or as a long-term treatment option to prevent worsening of heart failure in earlier stages.