Gene interactions and pathways from curated databases and text-mining
Arterioscler Thromb Vasc Biol 2005, PMID: 15802620

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

Taniyama, Yoshihiro; Hitomi, Hirofumi; Shah, Anand; Alexander, R Wayne; Griendling, Kathy K

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).

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.

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Text Mining Data

Akt ⊣ insulin receptor substrate-1 (IRS-1): " Recently, serine phosphorylation and degradation of insulin receptor substrate-1 (IRS-1) were shown to inhibit Akt activation and reduce glucose uptake "

Akt → insulin: " 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 "

Manually curated Databases

In total, 1 gene pairs are associated to this article in curated databases