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(Circulation Research. 2004;94:1211.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Angiotensin II Impairs the Insulin Signaling Pathway Promoting Production of Nitric Oxide by Inducing Phosphorylation of Insulin Receptor Substrate-1 on Ser³¹² and Ser⁶¹⁶ in Human Umbilical Vein Endothelial Cells

Francesco Andreozzi, Emanuela Laratta, Angela Sciacqua, Francesco Perticone, Giorgio Sesti

From the Department of Clinical and Experimental Medicine, University Magna Græcia of Catanzaro, Italy.

Correspondence to Francesco Perticone, Dipartimento di Medicina Sperimentale e Clinica "Gaetano Salvatore," Via Tommaso Campanella, 115, 88100 Catanzaro, Italy. E-mail perticone{at}unicz.it

It has been suggested that serine (Ser) phosphorylation of insulin receptor substrate-1 (IRS-1) decreases the ability of IRS-1 to be phosphorylated on tyrosine, thereby attenuating insulin signaling. There is evidence that angiotensin II (AII) may impair insulin signaling to the IRS-1/phosphatydilinositol 3-kinase (PI 3-kinase) pathway by enhancing Ser phosphorylation. Insulin stimulates NO production by a pathway involving IRS-1/PI3-kinase/Akt/endothelial NO synthase (eNOS). We addressed the question of whether AII affects insulin signaling involved in NO production in human umbilical vein endothelial cells and tested the hypothesis that the inhibitory effect of AII on insulin signaling was caused by increased site-specific Ser phosphorylation in IRS-1. Exposure of human umbilical vein endothelial cells to AII resulted in inhibition of insulin-stimulated production of NO. This event was associated with impaired IRS-1 phosphorylation at Tyr⁶¹² and Tyr⁶³², two sites essential for engaging the p85 subunit of PI3-kinase, resulting in defective activation of PI 3-kinase, Akt, and eNOS. This inhibitory effect of AII was reversed by the type 1 receptor antagonist losartan. AII increased c-Jun N-terminal kinase (JNK) and extracellular signal–regulated kinase (ERK) 1/2 activity, which was associated with a concomitant increase in IRS-1 phosphorylation at Ser³¹² and Ser⁶¹⁶, respectively. Inhibition of JNK and ERK1/2 activity reversed the negative effects of AII on insulin-stimulated NO production. Our data suggest that AII, acting via the type 1 receptor, increases IRS-1 phosphorylation at Ser³¹² and Ser⁶¹⁶ via JNK and ERK1/2, respectively, thus impairing the vasodilator effects of insulin mediated by the IRS-1/PI 3-kinase/Akt/eNOS pathway.

Key Words: endothelium • angiotensin II • nitric oxide • insulin

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