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

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) ␤ -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 AT 1 antagonist losartan or AT 2 antagonist PD123319. AII increased the serine phosphorylation of both the IR ␤ -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. (

Protein Kinase C-ζ Phosphorylates Insulin Receptor Substrate-1 and Impairs Its Ability to Activate Phosphatidylinositol 3-Kinase in Response to Insulin

“…Consistent with a negative feedback role, we observed that the overexpression of PKC-significantly impaired insulin-stimulated tyrosine phosphorylation of IRS-1. These results are in keeping with studies showing that increased serine phosphorylation of IRS-1 secondary to other stimuli is accompanied by impairment in the ability of IRS-1 to undergo tyrosine phosphorylation after insulin stimulation (15)(16)(17)(18)(19)(20)(21)(22)43). In addition, there was some specificity to the impairment of IRS-1 function because the interaction between IRS-1 and SHP-2 appeared to be unaffected by the overexpression of PKC-.…”

“…IRS-1 is also extensively phosphorylated on serine residues, and modulation of IRS-1 serine phosphorylation is observed in response to the treatment of cells with a variety of agents, including insulin (13,14), tumor necrosis factor ␣ (15-17), PDGF (18), angiotensin II (19), phorbol esters (20,21), and okadaic acid (14,22). Interestingly, IRS-1 has recently been identified as a substrate for both Akt and GSK-3, Ser/Thr kinases downstream from PI 3-kinase that participate in the metabolic actions of insulin (23,24).…”

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

“…The main player in this connection is Ang II acting through the AT1R (Velloso et al 2006, Folli et al 1997, Jandeleit-Dahm et al 2005. This correlates well with the beneficial effect of Ang II receptor type 1 (AT1R) blockers (e.g.…”

Insulin-like Growth Factor-I-stimulated Insulin Receptor Substrate-1 Negatively Regulates Src Homology 2 Domain-containing Protein-tyrosine Phosphatase Substrate-1 Function in Vascular Smooth Muscle Cells

“…IRS-1 degradation has been extensively studied in insulin-sensitive cell types, such as adipocytes and skeletal muscle cells and also in these tissues in animal models (13,31,(42)(43)(44). Hyperglycemia-induced IRS-1 down-regulation has been shown in vascular smooth muscle following PKC activation (45), ␤-adrenergic stimulation (46), and angiotensin II exposure (47,48). Exposure to growth factors, including IGF-I, also enhances IRS-1 degradation in a variety of cells (25,26,49,50).…”