Phosphoinositide 3-kinase Akt signaling pathway interacts with protein kinase C[beta]2 in the regulation of physiologic developmental hypertrophy and heart function

The phosphoinositide 3-kinase (PI3-kinase)-protein kinase B (Akt) signaling pathway is essential in the induction of physiological cardiac hypertrophy. In contrast, protein kinase C [beta]2 (PKC[beta]2) is implicated in the development of pathological cardiac hypertrophy and heart failure. Thus far, no clear association has been demonstrated between these two pathways. In this study, we examined the potential interaction between the PI3-kinase and PKC[beta]2 pathways by crossing transgenic mice with cardiac specific expression of PKC[beta]2, constitutively active (ca) PI3-kinase, and dominant-negative (dn) PI3-kinase. In caPI3-kinase/PKC[beta]2 and dnPI3-kinase/PKC[beta]2 double-transgenic mice, the heart weight-to-body weight ratios and cardiomyocyte sizes were similar to those observed in caPI3-kinase and dnPI3-kinase transgenic mice, respectively, suggesting that the regulation of physiological developmental hypertrophy via modulation of cardiomyocyte size proceeds through the PI3-kinase pathway. In addition, we observed that caPI3-kinase/ PKC[beta]2 mice showed improved cardiac function while the function of dnPI3-kinase/PKC[beta]2 mice was similar to that of the PKC[beta]2 group. PKC[beta]2 protein levels in both dnPI3-kinase/PKC[beta]2 and PKC[beta]2 mice were significantly upregulated. Interestingly, however, PKC[beta]2 protein expression was significantly attenuated in caPI3-kinase/PKC[beta]2 mice. PI3-kinase activity measured by Akt phosphorylation was not affected by PKC[beta]2 overexpression. These data suggest a potential interaction between these two pathways in the heart, where Pl3-kinase is predominantly responsible for the regulation of physiological developmental hypertrophy and may act as an upstream modulator of PKC[beta]2 with the potential for rescuing the pathological cardiac dysfunction induced by overexpression of PKC[beta]. transgenic mice; constitutive active; dominant negative; protein kinase B