Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels: A potential role for serine phosphorylation in insulin/angiotensin II crosstalk

Franco Folli, C. Ronald Kahn, Hans Hansen, Julie L. Bouchie, Edward P. Feener

Research output: Contribution to journalArticlepeer-review

390 Scopus citations

Abstract

To investigate potential interactions between angiotensin II (AII) and the insulin signaling system in the vasculature, insulin and AII regulation of insulin receptor substrate-1 (IRS-1) phosphorylation and phosphatidylinositol (PI) 3-kinase activation were examined in rat aortic smooth muscle cells. Pretreatment of cells with AII inhibited insulin- stimulated PI 3-kinase activity associated with IRS-1 by 60%. While AII did not impair insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) β-subunit, it decreased insulin-stimulated tyrosine phosphorylation of IRS-1 by 50%. AII inhibited the insulin-stimulated association between IRS-1 and the p85 subunit of PI 3-kinase by 30-50% in a dose-dependent manner. This inhibitory effect of AII on IRS-1/PI 3-kinase association was blocked by the AII receptor antagonist saralasin, but not by AT1 antagonist losartan or AT2 antagonist PD123319. AII increased the serine phosphorylation of both the IR β-subunit and IRS-1. In vitro binding experiments showed that autophosphorylation increased IR binding to IRS-1 from control cells by 2.5-fold versus 1.2-fold for IRS-1 from AII-stimulated cells, suggesting that AII stimulation reduces IRS-1's ability to associate with activated IR. In addition, AII increased p85 serine phosphorylation, inhibited the total pool of p85 associated PI 3-kinase activity, and decreased levels of the p50/p55 regulatory subunit of PI 3-kinase. These results suggest that activation of the renin-angiotensin system may lead to insulin resistance in the vasculature.

Original languageEnglish (US)
Pages (from-to)2158-2169
Number of pages12
JournalJournal of Clinical Investigation
Volume100
Issue number9
DOIs
StatePublished - Nov 1 1997

Keywords

  • Angiotensin II
  • Insulin receptor substrate-1
  • Insulin resistance
  • Phosphatidylinositol 3- kinase
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Medicine(all)

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