Published online before print March 25, 2004, doi: 10.1161/01.RES.0000126501.34994.96
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on October 17, 2003
Revised on March 1, 2004
Accepted on March 15, 2004
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 ;
From the Department of Clinical and Experimental Medicine, University Magna Græcia of Catanzaro, Italy.
* To whom correspondence should be addressed. 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
This article has been cited by other articles:
 |
|
 |
|
  S. Lee, E. G. Lynn, J.-a Kim, and M. J. Quon Protein Kinase C-{zeta} Phosphorylates Insulin Receptor Substrate-1, -3, and -4 But Not -2: Isoform Specific Determinants of Specificity in Insulin Signaling Endocrinology, May 1, 2008; 149(5): 2451 - 2458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Perticone, R. Maio, A. Sciacqua, F. Andreozzi, G. Iemma, M. Perticone, C. Zoccali, and G. Sesti Endothelial Dysfunction and C-Reactive Protein Are Risk Factors for Diabetes in Essential Hypertension Diabetes, January 1, 2008; 57(1): 167 - 171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. H. Schulman, M.-S. Zhou, E. A. Jaimes, and L. Raij Dissociation between metabolic and vascular insulin resistance in aging Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H853 - H859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Andreozzi, E. Laratta, C. Procopio, M. L. Hribal, A. Sciacqua, M. Perticone, C. Miele, F. Perticone, and G. Sesti Interleukin-6 Impairs the Insulin Signaling Pathway, Promoting Production of Nitric Oxide in Human Umbilical Vein Endothelial Cells Mol. Cell. Biol., March 15, 2007; 27(6): 2372 - 2383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. K. Mehta and K. K. Griendling Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system Am J Physiol Cell Physiol, January 1, 2007; 292(1): C82 - C97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Lee and L. Ragolia AKT phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1355 - C1365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Clavreul, M. M. Bachschmid, X. Hou, C. Shi, A. Idrizovic, Y. Ido, D. Pimentel, and R. A. Cohen S-Glutathiolation of p21ras by Peroxynitrite Mediates Endothelial Insulin Resistance Caused by Oxidized Low-Density Lipoprotein Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2454 - 2461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-M. Samuelsson, E. Bollano, R. Mobini, B.-M. Larsson, E. Omerovic, M. Fu, F. Waagstein, and A. Holmang Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H787 - H796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nigro, N. Osman, A. M. Dart, and P. J. Little Insulin Resistance and Atherosclerosis Endocr. Rev., May 1, 2006; 27(3): 242 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-a Kim, M. Montagnani, K. K. Koh, and M. J. Quon Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms Circulation, April 18, 2006; 113(15): 1888 - 1904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mussig, H. Staiger, H. Fiedler, K. Moeschel, A. Beck, M. Kellerer, and H.-U. Haring Shp2 Is Required for Protein Kinase C-dependent Phosphorylation of Serine 307 in Insulin Receptor Substrate-1 J. Biol. Chem., September 23, 2005; 280(38): 32693 - 32699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Watanabe, J. Suzuki, H. Yamawaki, V. K. Sharma, S.-S. Sheu, and B. C. Berk Losartan Metabolite EXP3179 Activates Akt and Endothelial Nitric Oxide Synthase via Vascular Endothelial Growth Factor Receptor-2 in Endothelial Cells: Angiotensin II Type 1 Receptor-Independent Effects of EXP3179 Circulation, September 20, 2005; 112(12): 1798 - 1805. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M R Abdollahi, T R Gaunt, H E Syddall, C Cooper, D I W Phillips, S Ye, and I N M Day Angiotensin II type I receptor gene polymorphism: anthropometric and metabolic syndrome traits J. Med. Genet., May 1, 2005; 42(5): 396 - 401. [Abstract] [Full Text] [PDF]
|
|