Transgenic overexpression of constitutively active protein kinase C ε causes concentric cardiac hypertrophy

To test the hypothesis that activation of the protein kinase C (PKC) epsilon isoform leads to cardiac hypertrophy without failure, we studied transgenic mice with cardiac-specific overexpression of a constitutively active mutant of the PKC epsilon isoform driven by an cr-myosin heavy chain promoter. In transgenic mice, the protein level of PKC epsilon in heart tissue was increased 9-fold. There was a 6-fold increase of the membrane/cytosol ratio, and PKC activity in the membrane fraction was 4.2-fold compared with wild-type mice. The heart weight was increased by 28%, and upregulation of the mRNA for P-myosin heavy chain and alpha-skeletal actin was observed in transgenic mouse hearts. Echocardiography demonstrated increased anterior and posterior wall thickness with normal left ventricular function and dimensions, indicating concentric cardiac hypertrophy. Isolated cardiomyocyte mechanical function was slightly decreased, and Ca2+ signals were markedly depressed in transgenic mice, suggesting that myofilament sensitivity to Ca2+ was increased. No differences were observed in either the levels of cardiac Ca2+-handling proteins or the degree of cardiac regulatory protein phosphorylation between wild-type and transgenic mice. Unlike mice with PKC beta(2) overexpression, transgenic mice with cardiac-specific overexpression of the active PKC epsilon mutant demonstrated concentric hypertrophy with normal in vivo cardiac function. Thus, PKC isoforms may play differential functional roles in cardiac hypertrophy and failure.