Opposing cardioprotective actions and parallel hypertrophic effects of δPKC and εPKC

Conflicting roles for protein kinase C (PKC) isozymes in cardiac disease have been reported. Here, delta PKC-selective activator and inhibitor peptides were designed rationally, based on molecular modeling and structural homology analyses. Together with previously identified activator and inhibitor peptides of epsilon PKC, delta PKC peptides were used to identify cardiac functions of these isozymes. In isolated cardiomyocytes, perfused hearts, and transgenic mice, delta PKC and epsilon PKC had opposing actions on protection from ischemia-induced damage. Specifically, activation of epsilon PKC caused cardioprotection whereas activation of delta PKC increased damage induced by ischemia in vitro and in vivo. In contrast, delta PKC and epsilon PKC caused identical nonpathological cardiac hypertrophy; activation of either isozyme caused nonpathological hypertrophy of the heart. These results demonstrate that two related PKC isozymes have both parallel and opposing effects in the heart, indicating the danger in the use of therapeutics with nonselective isozyme inhibitors and activators. Moreover, reduction in cardiac damage caused by ischemia by perfusion of selective regulator peptides of PKC through the coronary arteries constitutes a major step toward developing a therapeutic agent for acute cardiac ischemia.