Insulin Potentiates Platelet-Derived Growth Factor Action in Vascular Smooth Muscle Cells**This work was supported by grants from the VA Research Service, the NIH (HL-48920 to R.N., HD-24497–06 to J.S.), PO-1-HL-55798 (to J.N. and R.N.), jointly funded by the NIH and the Juvenile Diabetes Foundation, the American Heart Association, a fellowship support from the American Heart Association (to M.G.), HealthONE Foundation: Diabetes and Endocrine Research and Education Fund, and Foundation for Biomedical Education and Research.

Correlative studies have indicated that hyperinsulinemia is present in many individuals with atherosclerosis. Insulin resistance has also been linked to cardiovascular disease. It has proved to be difficult to decipher whether hyperinsulinemia or insulin resistance plays the most important role in the pathogenesis of atherosclerosis and coronary artery disease. In this study, we demonstrate that insulin increases the amount of farnesylated p21Ras in vascular smooth muscle cells (VSMC), thereby augmenting the pool of cellular Ras available for activation by platelet-derived growth factor (PDGF). In VSMC incubated with insulin for 24 h, PDGF's influence on GTP-loading of Ras was significantly increased. Furthermore, in cells preincubated with insulin, PDGF increased thymidine incorporation by 96% as compared with a 44% increase in control cells (a 2-fold increment). Similarly, preincubation of VSMC with insulin increased the ability of PDGF to stimulate gene expression of vascular endothelial growth factor 5- to 8-fold. The potentiating influence of insulin on PDGF action was abrogated in the presence of a farnesyltransferase inhibitor. Thus, the detrimental influence of hyperinsulinemia on the arterial wall may be related to the ability of insulin to augment farnesyltransferase activity and provide greater amounts of farnesylated p21Ras for stimulation by various growth promoting agents.