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Endocrinology Vol. 139, No. 10 4067-4072
Copyright © 1998 by The Endocrine Society

ARTICLES

Insulin Potentiates Platelet-Derived Growth Factor Action in Vascular Smooth Muscle Cells1

Marc L. Goalstone, Rama Natarajan, Paul R. Standley, Mary F. Walsh, J. Wayne Leitner, Kirsten Carel, Steven Scott, Jerry Nadler, James R. Sowers and Boris Draznin

The Department of Diabetes, Endocrinology and Metabolism (R.N., S.S., J.N.), City of Hope Medical Center, Duarte, California 91010; Research Service Detroit VA Medical Center and Department of Medicine (P.R.S., M.F.W., J.R.S.), Wayne State University, 48202; Research Service (M.L.G., J.W.L., K.C., B.D.), Denver VA Medical Center and Department of Medicine University of Colorado Health Sciences Center, Denver, Colorado 80220

Address all correspondence and requests for reprints to: Boris Draznin, M.D., Ph.D., VA Hospital (151), 1055 Clermont Street, Denver, Colorado 80220. E-mail: bdraznin{at}sembilan.uchsc.edu

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.




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