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

J Clin Invest. 1997 Nov 1;100(9):2158-69. doi: 10.1172/JCI119752.


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) beta-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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin II / physiology*
  • Animals
  • Aorta / physiology
  • Cells, Cultured
  • Insulin / physiology*
  • Insulin Receptor Substrate Proteins
  • Muscle, Smooth, Vascular / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Phosphoserine / metabolism*
  • Phosphotyrosine / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Insulin / metabolism
  • Receptors, Angiotensin / physiology
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Signal Transduction
  • Tetradecanoylphorbol Acetate / pharmacology


  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Phosphoproteins
  • Receptors, Angiotensin
  • Angiotensin II
  • Phosphoserine
  • Phosphotyrosine
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin
  • Receptors, Platelet-Derived Growth Factor
  • Tetradecanoylphorbol Acetate