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

Abstract

Background-Enzymatic, nonoxidative modification transforms LDL to an atherogenic molecule (E-LDL) that activates complement and macrophages and is present in early atherosclerotic lesions. Methods and Results-We report on the atherogenic effects of E-LDL on human vascular smooth muscle cells (SMC).E-LDL accumulated in these cells, and this was accompanied by selective induction of monocyte chemotactic protein-1 in the absence of effects on the expression of interleukin (IL)-8, RANTES, or monocyte inflammatory proteins-1␣ and -␤). Furthermore, E-LDL stimulated the expression of gp130, the signal-transducing chain of the IL-6 receptor (IL-6R) family, and the secretion of IL-6. E-LDL invoked mitogenic effects on SMC through 2 mechanisms. First, an autocrine mitogenic circuit involving platelet-derived growth factor and fibroblast growth factor-␤ was induced. Second, upregulation of gp130 rendered SMC sensitive to transsignaling through the IL-6/sIL-6R activation pathway. Because E-LDL promoted release of both IL-6 and sIL-6R from macrophages, application of macrophage cell supernatants to prestimulated SMC provoked a pronounced and sustained proliferation of the cells. Conclusions-E-LDL can invoke alterations in SMC that are characteristic of the evolving atherosclerotic lesion.

Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading

“…3 and 4A), therefore, suggests that cholesterol may lead to the alteration of SMCs to a state associated with features that are proatherogenic (27). Consistent with this notion is the report that enzymatically degraded, nonoxidized LDL induced human vascular SMC activation and foam-cell transformation, with the authors interpreting the data as evidence for a de-differentiation process (10). In light of the present results for macrophage-related proteins (see below), rather than representing a de-differentiating process, cholesterol loading may be more appropriately considered as part of a transdifferentiation program.…”

“…Although SMCs have previously been induced to accumulate cholesterol in vitro (8)(9)(10), for either in vitro or in vivo SMC foam cells, information is scant about phenotypic changes at the protein or RNA level. The results of the present study show that, with cholesterol loading in vitro, SMCs rapidly assume a foam-cell appearance and lose the expression of commonly accepted markers of the SMC phenotype.…”

“…Another possible explanation for these results is that cholesterol accumulation per se is not an inflammatory stimulus or that it is, but that induction of inflammatory molecules occurs at a later time. Support for the former possibility comes from the above-cited study (10), in which activation of SMCs was accomplished by delivery of cholesterol in the form of modified LDL [which contains the inflammatory factors (31,32)], and from studies by Lawn and colleagues (33), which have shown that loading of macrophage cell lines with oxidized LDL leads to increased expression of inflammatory genes and greater responsiveness of these genes to lipopolysaccharide stimulation (34).…”

“…7, the preferential increase in FC content either tended to further decrease or significantly increase, respectively, SMC or macrophage-related gene expression associated with cholesterol loading, although the degree of the enhancement was variable depending on the gene (i.e., greater for ␣-actin or CD68 than for ␣-tropomyosin or Mac-2, respectively). demonstrated in vitro (8,10) and in atherosclerotic plaques (e.g., ref. 7), these cells are usually assumed to occur relatively late in lesion development.…”

High-Density Lipoprotein Inhibits the Uptake of Modified Low- Density Lipoprotein and the Expression of CD36 and FcγRI

“…In the case of mLDL, the uptake and subsequent formation of foam cells can be either a rapid process involving already present receptors or a delayed process with the participation of mLDL-inducible receptors [13][14][15][16] . Modifications of LDL involve both oxidative modifications, caused by oxygen reactive radical species, and enzymatic alterations processed by serumor cell-associated proteolytic enzymes 4,[17][18][19][20] . These enzyme-mediated processes are likely to occur concomitantly with or independently of oxidation.…”