Mevalonate deprivation impairs IGF-I/insulin signaling in human vascular smooth muscle cells

Abstract

3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (statins) are therapeutically used to lower plasma cholesterol levels. In addition, these drugs can block vascular smooth muscle cell (VSMC) proliferation. The present study addressed the question whether the inhibitory effect of lovastatin on premitotic DNA synthesis correlates with a downregulation of c- fos mRNA levels, a marker of signaling efficiency, in human SMC. Here we show that in human SMC exposed to individual growth factors (platelet-derived growth factor, epidermal growth factor, α-thrombin, insulin, insulin-like growth factor I (IGF-I)) and human serum, the maximal [ 3H]thymidine incorporation and c- fos mRNA expression are closely correlated. Only α-thrombin elicited overexpression of c- fos as compared with its effect on [ 3H]thymidine incorporation. Lovastatin efficiently inhibited [ 3H]thymidine uptake promoted by all mitogens tested (76–87%); however, it significantly inhibited upregulation of c- fos mRNA levels induced only by insulin (33–67%, P<0.05) and IGF-I (31–57%, P<0.05). This inhibition was overcome by mevalonate and geranylgeraniol, and partially by farnesol. c- fos mRNA expression induced by 4- β-phorbol-12-myristate-13-acetate, an activator of protein kinase C, was insensitive to lovastatin treatment. Thus, in human vascular SMC, lovastatin impairs premitotic DNA synthesis induced by growth factors, but only c- fos expression promoted by insulin and IGF-I. These data indicate that statin-sensitive and -insensitive pathways seem to be involved in the regulation of c- fos in the response of human SMC to proliferative stimuli, and suggest a prominent role of isoprenylated proteins in the activation of VSMC through the IGF-I/insulin dependent pathways.