Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells
Abstract
Insulin exerts a vasodilatory effect through the release of nitric oxide (NO) from the endothelium. We have recently demonstrated that insulin also inhibits the expression of intracellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), 2 major proinflammatory mediators, by human aortic endothelial cells (HAEC) and the proinflammatory mediator, nuclear factor (NF-kappa B), in the nucleus in parallel with an increase in endothelial nitric oxide synthase (e-NOS) expression. The inhibition of ICAM-1 by insulin is NO dependent. Because tumor necrosis factor-alpha (TNF-a ) is proinflammatory and may thus inhibit the action of insulin at the endothelial cell level, we have now investigated whether TNF-a affects (1) insulin receptor content; (2) insulin receptor (IR) autophosphorylation induced by insulin, and (3) e-NOS expression by the endothelial cells. TNF-alpha (1 to 5 ng/mL) caused e-NOS inhibition in a dose-dependent fashion as measured by Western blotting. This inhibition was reduced with insulin addition. TNF-alpha also inhibited tyrosine autophosphorylation of the IR in HAEC induced by insulin and reduced IR beta-subunit protein expression in HAEC. These effects of insulin and TNF-alpha were inde...Continue Reading
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