Abstract 260: Loss of Insulin Signaling in Vascular Endothelium Accelerates Atherosclerosis in Apolipoprotein E Knockout Mice
The role of insulin action on the vasculature in patients at risk for atherothrombotic disease remains controversial. Insulin regulates several endothelium-derived factors, including nitric oxide and endothelin-1, generally considered to prevent and promote atherosclerosis, respectively. Hyperinsulinemia is a cardiovascular risk factor, either because of deleterious effects of insulin directly on the vasculature, or because insulin has beneficial vascular effects that are blunted by insulin resistance in association with hyperinsulinemia. This has critical implications for patients with diabetes treated with insulin, as an adverse effect of insulin on the vasculature could offset effects that prevent atherosclerosis through control of hyperglycemia and dyslipidemia. To determine whether the overall effect of endothelial insulin signaling is pro- or anti-atherosclerotic, we have created mice on an apolipoprotein E null background with (VENIRKO/apoE null) or without conditional deletion of the insulin receptor in endothelium, using the Cre/loxP system. After 16 weeks on a “Western diet” with 21% (w/w) fat, atherosclerotic lesion area in the descending aorta was twice as large in male VENIRKO/apoE null mice compared to littermate controls (5.5±1.1% and 11.9±2.3%, respectively, p=0.01). This change in atherosclerotic lesion burden could not be explained by systemic changes in metabolism or insulin action. Weight gain in VENIRKO/apoE null mice was smaller than controls (body mass 91% of controls after 16 weeks on the diet). There were no differences in serum cholesterol and triglycerides or in lipoprotein fractions. Fasting blood glucose and serum insulin were not different, and insulin sensitivity and glucose tolerance during intraperitoneal insulin and glucose tolerance tests were not decreased in VENIRKO/apoE null mice compared to controls. In conclusion, loss of endothelial insulin signaling accelerates atherosclerosis without adversely affecting systemic metabolic parameters. This has potentially great importance for prevention of cardiovascular disease in patients with insulin resistance and diabetes because the mechanisms and optimal treatment of insulin resistance in endothelium may be different than in other tissues.