Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin II

作者：Taniyama Y; Hitomi H; Shah A; Alexander RW; Griendling KK^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2005, 25(6): 1142-1147.

DOI：10.1161/01.ATV.0000164313.17167.df

• vascular smooth muscle
• angiotensin II
• insulin
• IRS-1
• insulin resistance
• phosphoinositide
• dependent kinase-1

Objective - Angiotensin II has been implicated in the pathogenesis of the vascular complications of insulin resistance. Recently, serine phosphorylation and degradation of insulin receptor substrate-1 (IRS-1) were shown to inhibit Akt activation and reduce glucose uptake. Therefore, we examined the effects of chronic angiotensin II treatment on IRS-1 phosphorylation and protein expression in vascular smooth muscle cells (VSMCs).
Methods and Results - Using Western analysis, we found that angiotensin II ( 100 nmol/L; 18 hours) caused a 61 +/- 5% degradation of IRS-1 and abolished insulin-induced activation of Akt. Phosphorylation of IRS-1 on Ser307, which leads to subsequent IRS-1 degradation, was stimulated by angiotensin II. This phosphorylation was blocked by the Src inhibitor PP1 and by the antioxidants N-acetylcysteine and ebselen. Stable overexpression of catalase abrogated angiotensin II - induced IRS-1 phosphorylation and IRS-1 degradation. Similarly, a mutant phosphoinositide-dependent kinase-1 (PDK1) that cannot associate with Src abolished IRS-1 phosphorylation and degradation induced by angiotensin II. Proteasome inhibitors also prevented IRS-1 degradation.
Conclusions - Thus, angiotensin II decreases IRS-1 protein levels in VSMCs via Src, PDK1, and reactive oxygen species - mediated phosphorylation of IRS-1 on Ser307 and subsequent proteasome-dependent degradation. These events impair insulin signaling and provide a molecular basis for understanding the clinical observation that angiotensin II type 1 receptor antagonists improve insulin resistance and its associated vasculopathies.

• 出版日期2005-6