Effect of persistent activation of phosphoinositide 3-kinase on heart.

Aims: Insulin/insulin-like growth factor-1 (IGF-1) signaling plays an important role in many biological processes. The class IA isoform of phosphoinositide 3-kinase (PI3K) is an important downstream effector of the insulin/IGF-1 signaling pathway. The aim of this study is to examine the effect of persistent activation of PI3K on gene expression and markers of cellular senescence in murine hearts.

Main Methods: Transgenic mice expressing a constitutively active PI3K in a heart-specific manner were analyzed at the ages of 3 and 20 months. Effects of persistent activation of PI3K on gene expression were comprehensively analyzed using microarrays.

Key Findings: Upon comprehensive gene expression profiling, the genes whose expression was increased included those for several heat shock chaperons. The amount and nuclear localization of a forkhead box O (FOXO) protein was increased. In addition, the gene expression of insulin receptor substrate-2 decreased, and that of phosphatase and tensin homolog deleted on chromosome ten (PTEN) increased, suggesting that the persistent activation of PI3K modified the expression of molecules of insulin/IGF-1 signaling. The expression of markers of cellular senescence, such as senescence-associated beta-galactosidase activity, cell cycle inhibitors, proinflammatory cytokines, and lipofuscin, did not differ between old wild-type and caPI3K mice.

Significance: The persistent activation of PI3K modified the expression of molecules of insulin/IGF-1 signaling pathway in a transgenic mouse line. Markers of cellular senescence were not changed in the aged mutant mice.