Am J Physiol Cell Physiol AJP: Endocrinology and Metabolism
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Am J Physiol Cell Physiol 280: C1057-C1065, 2001;
0363-6143/01 $5.00
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Vol. 280, Issue 5, C1057-C1065, May 2001

TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells

Francis Kim, Byron Gallis, and Marshall A. Corson

Department of Medicine, Division of Cardiology, Harborview Medical Center, University of Washington, Seattle, Washington 98104

Endothelial cells release nitric oxide (NO) acutely in response to increased "flow" or fluid shear stress (FSS), and the increase in NO production is correlated with enhanced phosphorylation and activation of endothelial nitric oxide synthase (eNOS). Both vascular endothelial growth factor and FSS activate endothelial protein kinase B (PKB) by way of incompletely understood pathway(s), and, in turn, PKB phosphorylates eNOS at Ser-1179, causing its activation. In this study, we found that either FSS or insulin stimulated insulin receptor substrate-1 (IRS-1) tyrosine and serine phosphorylation and increased IRS-1-associated phosphatidylinositol 3-kinase activity, phosphorylation of PKB Ser-473, phosphorylation of eNOS Ser-1179, and NO production. Brief pretreatment of bovine aortic endothelial cells with tumor necrosis factor-alpha (TNF-alpha ) inhibited the above described FSS- or insulin-stimulated protein phosphorylation events and almost totally inhibited FSS- or insulin-stimulated NO production. These data indicate that FSS and insulin regulate eNOS phosphorylation and NO production by overlapping mechanisms. This study suggests one potential mechanism for the development of endothelial dysfunction in disease states with alterations in insulin regulation and increased TNF-alpha levels.

insulin receptor substrate-1; tyrosine phosphorylation; phosphatidylinositol 3-kinase; endothelial nitric oxide synthase phosphorylation; tumor necrosis factor-alpha ; nitric oxide


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