Enzymatically degraded, nonoxidized LDL induces human vascular smooth muscle cell activation, foam cell transformation, and proliferation

Background-Enzymatic, nonoxidative modification transforms LDL to an athero genic molecule (E-LDL) that activates complement and macrophages and is pre sent 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 t his 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 alpha and -beta) Furthermore, E-LDL s timulated 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 mitogeni c effects on SMC through 2 mechanisms. First, an autocrine mitogenic circui t involving platelet-derived growth factor and fibroblast growth factor-bet a was induced. Second, upregulation of gp130 rendered SMC sensitive to tran ssignaling through the IL-6/sIL-GR activation pathway. Because E-LDL promot ed release of both IL-6 and sIL-6R from macrophages, application of macroph age cell supernatants to prestimulated SMC provoked a pronounced and sustai ned proliferation of the cells. Conclusions-E-LDL can invoke alterations in SMC that are characteristic of the evolving atherosclerotic lesion.