LIPOPROTEINS ARE MAJOR AND PRIMARY MITOGENS AND GROWTH PROMOTERS FOR HUMAN ARTERIAL SMOOTH-MUSCLE CELLS AND LUNG FIBROBLASTS IN-VITRO

Smooth muscle proliferation leading to excessive intimal thickening is of prime importance in atherosclerosis. Human arterial smooth muscle cells (SMCs) and human lung fibroblasts are rather insensitive to mito gens under plasma-free conditions in vitro. This prompted us to study the distribution and nature of the growth-promoting material in human plasma. SMCs were obtained from explants of human aortic media. More t han 80% of the growth-promoting activity of plasma was present in the lipoprotein (LP) fraction. The growth-promoting capacity of the differ ent LPs was determined on fractions isolated with density gradient ult racentrifugation. Cytotoxic effects appeared if low-density lipoprotei n (LDL) was not protected from oxidation and were aggravated with plat elet-derived growth factor (PDGF)-BB. Very-low-density lipoprotein, LD L, and high-density lipoprotein (HDL) stimulated DNA replication and c ell growth by themselves. The stimulation was considerable and equaled that obtained with PDGF-BB only. It was strongly increased in the pre sence of PDGF-BB. The effect on SMCs was not uniform for subfractions of HDL. A light portion inhibited growth in the absence but strongly s timulated it in the presence of PDGF-BB. For fibroblasts, HDL subfract ions had a uniform effect, suggesting a cell type-dependent difference . Addition of cholesterol or essential fatty acids did not induce a gr owth response similar to that of LPs. This speaks strongly against mer e nutritional supplementation as responsible for the mitogenic and gro wth-promoting effect of LPs and suggests that the effect may be more s pecific. Disordered LP metabolism is strongly related to atheroscleros is, and certain LPs have a potential role for the deposition of lipids . In addition to this, the distinct mitogenic and growth-stimulating e ffect of LPs by themselves, as demonstrated in the present report, sug gests a mechanism by which intimal thickening, which is a prerequisite for atherosclerosis, may be induced. The pronounced amplification of this effect with PDGF-BB, a substance that also has been implicated in atherogenesis, might promote growth leading to the excessive intimal thickening in the atherosclerotic plaque.