Published online before print March 31, 2005, doi: 10.1161/01.ATV.0000164313.17167.df
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© 2005 American Heart Association, Inc.
Vascular Biology |
Mechanisms of Reactive Oxygen Species–Dependent Downregulation of Insulin Receptor Substrate-1 by Angiotensin II
From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Ga.
Correspondence to Kathy K. Griendling, Emory University Division of Cardiology 319 WMB 1639 Pierce Dr, Atlanta, GA 30322. 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.
Angiotensin II and reactive oxygen species (ROS) mediate insulin resistance, but the underlying mechanisms are unclear. In vascular smooth muscle cells, angiotensin II induces IRS-1 phosphorylation and degradation via Src, PDK1, and ROS. These events impair insulin signaling and may explain the role of angiotensin II in diabetic vasculopathy.
Key Words: vascular smooth muscle • angiotensin II • insulin • IRS-1 • insulin resistance • phosphoinositide-dependent kinase-1
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