Submitted on May 27, 2008
Revised on December 16, 2008
Accepted on December 30, 2008
Phosphoinositide 3-kinase Akt signaling pathway interacts with protein kinase C
2 in the regulation of physiologic developmental hypertrophy and heart function
Debra L. Rigor1, Natalya Bodyak1, Soochan Bae1, Jun H. Choi1, Li Zhang1, Dmitry Ter-Ovanesyan1, Zhiheng He2, Julie R. McMullen1, Tetsuo Shioi1, Seigo Izumo3, George L. King4, and Peter M. Kang1*
1 Beth Israel Deaconess Medical Center
2 Joslin Diabetes Center
3 Novartis Institutes for Biomedical Research
4 Harvard Medical School
* To whom correspondence should be addressed. E-mail: pkang{at}bidmc.harvard.edu.
The phosphoinositide 3-kinase (PI3K)-Akt signaling pathway is essential in the induction of physiological cardiac hypertrophy. In contrast, protein kinase C beta 2 (PKC
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 PI3K and PKC2 pathways by crossing transgenic (Tg) mice with cardiac specific expression of PKC2, constitutively active PI3K and dominant negative PI3K. In caPI3K/PKC2 and dnPI3K/PKC2 double transgenic mice, the heart weight/body weight (HW/BW) ratios and cardiomyocyte sizes were similar to those observed in caPI3K and dnPI3K transgenic mice, respectively, suggesting that the regulation of physiologic developmental hypertrophy via modulation of cardiomyocyte size proceeds through the PI3K pathway. In addition, we observed that caPI3K/PKC2 mice showed improved cardiac function while the function of dnPI3K/PKC2 mice was similar to that of the PKC2 group. PKC2 protein levels in both dnPI3K/PKC2 and PKC2 mice were significantly upregulated. Interestingly, however, PKC2 protein expression was significantly attenuated in caPI3K/PKC2 mice. PI3K activity measured by Akt phosphorylation was not affected by PKC2 overexpression. These data suggest a potential interaction between these two pathways in the heart, where PI3K is predominantly responsible for the regulation of physiologic developmental hypertrophy and may act as an upstream modulator of PKC2 with the potential for rescuing the pathologic cardiac dysfunction induced by overexpression of PKC2.
