Lipoproteins are major and primary mitogens and growth promoters for human arterial smooth muscle cells and lung fibroblasts in vitro.

Abstract

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 mitogens under plasmafree 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 than 80% of the growth-promoting activity of plasma was present in the lipoprotein (LP) fraction. The growth-promoting capacity of the different LPs was determined on fractions isolated with density gradient ultracentrifugation. Cytotoxic effects appeared if low-density lipoprotein (LDL) was not protected from oxidation and were aggravated with platelet-derived growth factor (PDGF)-BB. Very-lowdensity lipoprotein, LDL, and high-density lipoprotein (HDL) stimulated DNA replication and cell growth by themselves. The stimulation was considerable and equaled that obtained with PDGF-BB only. It was strongly increased in the presence of PDGF-BB. The effect on SMCs was not uniform for subfractions of HDL. A light portion inhibited growth in the absence but strongly stimulated it in the presence of PDGF-BB. For fibroblasts, HDL subfractions had a uniform effect, suggesting a cell type-dependent difference. Addition of cholesterol or essential fatty acids did not induce a growth response similar to that of LPs. This speaks strongly against mere nutritional supplementation as responsible for the mitogenic and growth-promoting effect of LPs and suggests that the effect may be more specific. Disordered LP metabolism is strongly related to atherosclerosis, and certain LPs have a potential role for the deposition of lipids. In addition to this, the distinct mitogenic and growth-stimulating effect of LPs by themselves, as demonstrated in the present report, suggests 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. (Arterioscler Thromb. 1994;14:288-298.)

Evidence That Lipoproteins Are Carriers of Bioactive Factors

“…We demonstrated that although the effect of LDL on p44 mapk / p42 mapk phosphorylation was more pronounced than that of HDL and VLDL, both HDL and VLDL are able to induce similar effects in VSMC including DNA synthesis. Our results are in concordance with the findings of other investigators showing that not only LDL but also HDL 38,39 and VLDL 38 stimulate DNA synthesis in VSMC. It is also described that HDL is able to stimulate an increase of c-fos mRNA in VSMC.…”

Involvement of Neuron-Derived Orphan Receptor-1 (NOR-1) in LDL-Induced Mitogenic Stimulus in Vascular Smooth Muscle Cells: Role of CREB

“…The activation of CREB by LDL could be relevant beyond NOR-1 upregulation because recent papers argue for a main role of this transcription factor in VSMC survival/proliferation and vascular remodeling processes, 38 and CRE sites seem to be key in cyclin A and D1 transcriptional regulation. 39,40 In fact, we show that VLDLs, lipoproteins that also activate CREB and promote vascular cell proliferation, 8,9,41 also upregulate NOR-1 expression. Finally, oxLDL, a well-known inducer of VSMC proliferation through a general induction of cell cycle proteins mainly involving reactive oxygen species and the transcription factor nuclear factor B (NF-B), [42][43][44] had only a minor effect on NOR-1 upregulation.…”

Stimulation of mitogen activated protein kinase by LDL and oxLDL in human U‐937 macrophage‐like cells

“…Cellular proliferation has been reported to be stimulated by LDL in combination with serum [6,7] or with growth factors [8,9] and chemically modified LDLs, such as oxLDL and acLDL, induce macrophage growth [10]. Consistently, macrophage derived foam cells, generated by uptake of modified LDL through the scavenger receptor pathway [11], tend to proliferate in atherosclerotic lesions [12,13].…”

“…However, although there are numerous investigations which deal with mitogenic properties of lipoproteins [9,15], whether mitogenic activity is an intrinsic property of LDL or oxLDL is still a matter of debate. In this respect, our study was performed to examine direct lipoprotein induced effects on mitogen activated protein kinase.…”