Evidence for the inhibition of platelet-derived growth factor induced rat smooth muscle cells DNA synthesis by fenofibric acid at the Go/G1 cell cycle level

Abstract

It has been proposed that a platelet-derived growth factor (PDGF) may play an important role in the genesis of atherosclerosis by promoting proliferation of smooth muscle cells. The present study shows evidence that fenofibric acid inhibits the growth promoting activity of PDGF on cultured smooth muscle cells. When smooth muscle cells are in a quiescent state by feeding them a PDGF -and lipoproteins- deficient medium, addition of a platelet extract induces DNA synthesis in a synchronous fashion. A 6 hours' exposure of cells to this extract is sufficient for this effect. Fenofibric acid could inhibit this synthesis when the compound was present in the culture medium concomitantly with platelet extract. This result suggests that fenofibric acid target is a cellular event attendant on PDGF-induced growth promotion. Fenofibric acid is a hypolipidemic drug which inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCoA reductase) activity, the limiting step of endogenous cholesterol synthesis. If any endogenous cholesterol is available, smooth muscle cell cholesterol needs for proliferation can be supplied by LDL-cholesterol. As the addition of LDL to the culture medium did not overcome fenofibric acid inhibition, this demonstrates a cholesterol independent mechanism for the anti-PDGF growth promoting activity. The fact that fenofibric acid, a hypolipidemic drug, can also inhibit growth promoting activity of PDGF suggests that this drug can be effective on the prevention of atherosclerosis and cardiovascular diseases by at least two independent mechanisms.