on March 31, 2005
Published online before print March 31, 2005, doi: 10.1161/01.ATV.0000164313.17167.df
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Submitted on October 8, 2004
Accepted on March 16, 2005
Mechanisms of Reactive Oxygen Species-Dependent Downregulation of Insulin Receptor Substrate-1 by Angiotensin II
Yoshihiro Taniyama ;
From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Ga.
* To whom correspondence should be addressed. E-mail: kgriend{at}emory.edu.
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.
Key words: vascular smooth muscle • angiotensin II • insulin • IRS-1 • insulin resistance • phosphoinositide-dependent kinase-1
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