P175	Hyperinsulinemia and TNFα supress the expression of endothelial NO synthase but promote proatherogenic processes induced by insulin in endothelial cells.
1U.Bavendiek, 2R.Ebensperger, 1Chr.Dellwisch, 1D.Gottschalk, 1B.Schieffer
1Dept. of Cardiology & Angiology, Hannover Medical School, Hannover, DE; 2Dept. of Pharmacy, Pontificia Universidad Catolica de Chile, Santiago, CL.

Background: Typ 2 Diabetes mellitus is characterized by hyperinsulinemia, increased levels of inflammatory mediators, e. g. TNFα, and a marked increase of atherosclerosis. Therefore, the present study hypothesized, that mimicking hyperinsulinemia and exposure to inflammatory mediators such as TNFα attenuates the vasoprotective insulin-induced expression of endothelial nitric oxide synthase (eNOS) but promotes insulin-induced proatherogenic processes in endothelial cells. Methods & Results: Insulin (100 nM) markedly increased the protein expression of (eNOS) in human umbilical venous endothelial cells (EC, n=5, western blot). Surprisingly, insulin also induced protein expression of the proinflammatory chemokines MCP-1, IL-8 and GROα (protein array) in EC and conditioned media of insulin treated EC significantly induced the migration of monocytes (THP-1 cells, transwell migration assay) compared to media obtained from control treated EC (n=5, p<0.001). Importantly, insulin (100-1000 nM) did not directly stimulate the migration of monocytes. Pretreatment (18 h) of EC with insulin (100 nM) or TNFα (5 ng/ml) blunted the insulin-induced expression of eNOS. In contrast, the insulin-induced expression of chemokines (MCP-1, IL-8, GROα) as well as the promigratory effect of conditioned media obtained from insulin treated EC was not attenuated by pretreatment of EC with insulin or TNFα. (n=5). Conclusion: Mimicking hyperinsulinemia and exposure to inflammatory mediators in vitro promoted proatherogenic and attenuated vasoprotective actions of insulin in endothelial cells. Favoring the proatherogenic properties of insulin on the endothelium may represent a major pathomechanism involved in increased development of atherosclerosis and cardiovascular disease in patients with Typ 2 diabetes mellitus.

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