Animal studies have demonstrated that
hypercholesterolemia leads to the development of fibromuscular atherosclerotic lesions that are characterized by the intimal accumulation of
cholesterol esters in macrophage foam cells and focal proliferation of smooth muscle cells (SMCs). There is now convincing evidence that formation of foam cells occurs as a result of macrophage uptake of
oxidized low density lipoprotein (
LDL), but the processes linking
hypercholesterolemia to activation of SMC growth are less clear. In the present study, we demonstrated that native as well as
oxidized LDL stimulates
DNA synthesis in cultured human SMCs. Both native and
oxidized LDL enhances the expression of
platelet-derived growth factor (
PDGF) A-chain transcripts in the cells, suggesting that the mitogenic effect of the
lipoprotein preparations may be due to activation of autocrine or paracrine PDGF loops. Preincubation of SMCs with native and
oxidized LDL also increased the expression of PDGF alpha- and beta-receptors on SMCs and enhanced the responsiveness of the cells to exogenous PDGF. The maximal stimulatory effect of
oxidized LDL occurred at a concentration of 3 micrograms/ml, whereas that of native
LDL occurred
at 10 micrograms/ml, but otherwise no difference was observed between the native and
oxidized LDL preparations. The mitogenic effects of
LDL disappeared if the cells were exposed to the
lipoprotein preparations for more than 4 hours and was also effectively inhibited by
superoxide dismutase. The present results suggest that
LDL may influence the growth of SMCs by modulating the expression of growth-regulatory genes in the cells.