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.
Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels : a potential role for serine phosphorylation in insulin/angiotensin II crosstalk / F. Folli, C.R. Kahn, H. Hansen, J.L. Bouchie, E.P. Feener. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 100:9(1997), pp. 2158-2169.
|Titolo:||Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels : a potential role for serine phosphorylation in insulin/angiotensin II crosstalk|
|Parole Chiave:||angiotensin II, insulin, serine phosphorylation, insulin resistance, essential arterial hypertension, losartan, IRS-1, PI 3-kinase, AT1 receptor, AT2 receptor, insulin receptor, tyrosine phosphorylation, p85 regulatory subunit of PI 3-kinase|
|Settore Scientifico Disciplinare:||Settore MED/09 - Medicina Interna|
|Data di pubblicazione:||1-nov-1997|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1172/JCI119752|
|Appare nelle tipologie:||01 - Articolo su periodico|