Native and oxidized LDL enhances production of PDGF AA and the surface expression of PDGF receptors in cultured human smooth muscle cells.
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.
Stiko-Rahm
A
A
Department of Internal Medicine, Karolinska Hospital, Stockholm, Sweden.
Hultgårdh-Nilsson
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Regnström
J
J
Hamsten
A
A
Nilsson
J
J
D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis*; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor
D008077:Lipoproteins, LDL; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D004247:DNA; D017479:Receptors, Platelet-Derived Growth Factor