Growth-stimulating effect of lipoproteins on human arterial smooth-muscle cells and lung fibroblasts is due to Apo B-containing lipoproteins, type LDL and VLDL, and requires LDL receptors

Abstract

Excessive growth of the arterial smooth muscle is essential for the development of atherosclerosis and leads to arterial insufficiency in several other conditions. It is therefore important to elucidate the mechanisms that regulate the growth of the human arterial smooth-muscle cell, SMC. Like other untransformed cells, SMC require plasma for sustained growth in vitro. As found in an earlier study most of the material in plasma which stimulates SMC growth is related to the lipoproteins (LP), and is widespread among LP of different density classes. In the present study we investigated whether the growth-stimulating activity might be more specifically related to certain lipoproteins defined by criteria other than density or particle size. Activity was assayed using human SMC and human lung fibroblasts as both a change of culture size and DNA synthesis. The growth-stimulating activity was confined to apo B-containing LP, as defined by their strong affinity to heparin-Sepharose, electrophoretic beta-mobility, the presence of apo B and the absolute requirement of low density lipoprotein (LDL) receptors for the growth-stimulating effect to appear. It was strongly potentiated by PDGF-BB. A much higher level of LDL was required to initiate synthesis of DNA in SMC than in fibroblasts but at optimal LDL concentration the degree of activation was similar for both cell types. Apo B-containing LP are very powerfully related to atherosclerosis. As intimal thickening is a primary change in atherogenesis, the growth-stimulating effect of them may be of direct pathogenetic importance.

Hyaluronan Accumulation Is Elevated in Cultures of Low Density Lipoprotein Receptor-deficient Cells and Is Altered by Manipulation of Cell Cholesterol Content

“…As others have found, absence of functional LDL receptors results in reduced proliferation (41)(42)(43). High mass HA has been shown to inhibit smooth muscle cell proliferation (21).…”

“…Elevated Hyaluronan Accumulation by WHHL ASMC Cultures Is Independent of Cell Density and Serum Level-Because the amount of HA produced in cell culture is inversely proportional to the cell density (40) and WHHL cells grow more slowly than NZW cells (41)(42)(43) (Fig. 1B), we tested the effect of cell density on HA levels.…”

Enzymatically Degraded, Nonoxidized LDL Induces Human Vascular Smooth Muscle Cell Activation, Foam Cell Transformation, and Proliferation

“…19 -21 We detected no proliferative responses to native LDL, which stands in some disagreement with an earlier study. 20 In the absence of macrophages, E-LDLinduced proliferation appeared to ensue through an autocrine pathway involving PDGF and FGF-␤, as indicated from blocking experiments with antibodies. Arterial SMC express PDGF, 22,23 and the significance of this growth factor in atherosclerosis is supported by the restricted expression of PDGF receptors on the proliferating SMC subset in the intima, 24 whereas expression is absent on stationary SMC in the media.…”

Myofibroblast Involvement in Glycosaminoglycan Synthesis and Lipid Retention during Coronary Repair

“…Since atherogenic lipids have the ability to modify lesion content, their accumulation in the healing artery could be relevant to the process of coronary restenosis [6, 45]. Local interactions between PGs and apoB promote LDL oxidation which increases the influx of inflammatory cells, cellular proliferation and extracellular matrix synthesis [46, 47, 48]. The observed increase in neointimal formation in hyperlipemic animals further underscored detrimental effects of lipid and its modifications on the coronary repair process.…”