Abstract 142: Phosphoinositide 3-Kinase-AKT Signaling Pathway Interacts with Protein Kinase Cβ2 in the Determination of Cardiomyocyte Size and Heart Function
The phosphoinositide 3-kinase (PI3K)-Akt signaling pathway is essential in the determination of cardiomyocyte size, as well as the induction of physiological cardiac hypertrophy. In contrast, protein kinase C beta 2 (PKCβ2) is implied in the development of pathological cardiac hypertrophy and heart failure. Thus far, no clear association has been demonstrated between these pathways. In this study, we examine the potential interaction between the PI3K and PKCβ2 pathways by crossing transgenic (Tg) mice with cardiac specific expression of PKCβ2, constitutively active PI3K (caPI3K), and dominant negative PI3K (dnPI3K). In caPI3K/PKCβ2 and dnPI3K/PKCβ2 double transgenic mice, the heart weight/body weight (HW/BW) ratio and cardiomyocyte size were similar to that found in caPI3K and dnPI3K transgenic mice, respectively, suggesting that heart weight via modulation of cardiomyocyte size is through the PI3K pathway. However, the cardiomyocyte size in PKCβ2 mice was similar to the wild type (WT) group, thus the increased size observed in the hearts of PKCβ2 mice was not associated with an increase in cardiomyocyte size. In addition, we observed that caPI3K/PKCβ2 mice showed improved cardiac function, while the function of dnPI3K/PKCβ2 mice was similar to that of the PKCβ2 group. Analysis by Western blot revealed that PKCβ2 protein level in dnPI3K/PKCβ2 mice, as well as in PKCβ2 mice, was significantly upregulated. Interestingly, however, expression of PKCβ2 protein was completely attenuated in caPI3K/PKCβ2 mice. PI3K activity measured by Akt phosphorylation was not affected by PKCβ2 overexpression. These data suggest an existence of cross-talk between the PI3K and PKCβ2 pathways in the heart where PI3K is predominantly responsible for cell size determination. PI3K may act as an upstream modulator of PKCβ2, and could rescue the pathologic cardiac dysfunction by suppressing PKCβ2 expression.