Effect of persistent activation of phosphoinositide 3-kinase on heart

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• 作者：Shinichiro Niizuma^a ; ¹ ; Yasutaka Inuzuka^a ; ¹ ; Junji Okuda^a ; Takao Kato^a ; Tsuneaki Kawashima^a ; Yodo Tamaki^a ; Yoshitaka Iwanaga^a ; Yuki Yoshida^b ; Rie Kosugi^b ; Kayo Watanabe-Maeda^b ; Yoji Machida^b ; Shingo Tsuji^c ; Hiroyuki Aburatani^c ; Tohru Izumi^b ; Toru Kita^a ; Takeshi Kimura^a ; Tetsuo Shioi^a ; ^{tshioi@kuhp.kyoto-u.ac.jp}
• 关键词：Insulin ; Phosphoinositide 3-kinase ; Gene expression ; Aging
• 刊名：Life Sciences
• 出版年：2012
• 期刊代码：62_00243205
• 类别：imm
• 出版时间：20 April, 2012
• 卷：90
• 期：15-16
• 页码：619-628
• 文件大小：1193 K

摘要

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.