Native and oxidized LDL enhances production of PDGF AA and the surface expression of PDGF receptors in cultured human smooth muscle cells.

Abstract

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.

An Experimental Model of Tumor Dormancy Therapy for Advanced Head and Neck Carcinoma

“…It enhances PDGF-AA gene expression and PDGF receptor expression in vascular smooth muscle cells. 7) Probucol has a superoxide scavenging effect, inhibits the production of PDGF, and also protects LDL from oxidation, which potentially reduces smooth muscle cell proliferation. Probucol does not directly act on tumor cells in vitro, 2) but showed an antitumor effect in tumor-bearing nude mice via an anti-angiogenic action, which may induce cellular apoptosis as a result of decreased blood supply.…”

Minimally modified LDL upregulates endothelin type B receptors in rat coronary artery via ERK1/2 MAPK and NF-κB pathways

“…When only the lipid region of LDL is oxidized, mmLDL will be formed. The mmLDL induces monocyte adhesion to endothelial cells and endothelium dysfunction, promotes the formation of oxidized low density lipoprotein (oxLDL) and foam cells, enhances vascular cell migration and proliferation [1][2][3], and participates in atherosclerotic lesion formation; these effects increase the risk of cardiovascular disease, such as coronary heart disease, the leading cause of death worldwide. These biological effects occur through a mechanism involving the stimulation of the receptor-mediated signal transduction pathways [4].…”

Oxidized Low Density Lipoprotein and Lysophosphatidylcholine Stimulate Cell Cycle Entry in Vascular Smooth Muscle Cells

“…More recently multiple effects of oxidized LDL, related conceptually to cell proliferation, have been reported including the induction of platelet-derived growth factor-AA production and platelet-derived growth factor receptor expression in vascular smooth muscle cells (SMC) (21), induction of various growth factors in endothelial cells (1), and stimulation of increased DNA synthesis in macrophages (22) and smooth muscle cells (23)(24)(25). In some studies oxidized LDL-induced increases in cell number were also reported; however, in some, mitogenic levels of serum were also present (26) and in others cells were not previously rendered quiescent (23), leaving ambiguous the role of oxidized LDL as a mitogen.…”