Enzymatically degraded, nonoxidized LDL induces human vascular smooth muscle cell activation, foam cell transformation, and proliferation.
BACKGROUND
Enzymatic, nonoxidative modification transforms LDL to an atherogenic molecule (E-LDL) that activates complement and macrophages and is present in early atherosclerotic lesions.


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-1alpha and -beta). 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-beta 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.
Klouche
M
M
Institute of Medical Microbiology, University of Mainz, Germany. klouche@mail.uni-mainz.de
Rose-John
S
S
Schmiedt
W
W
Bhakdi
S
S
D000368:Aged; D001011:Aorta; D001161:Arteriosclerosis / Q000097:blood / Q000473:pathology*; D002455:Cell Division; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D008078:Cholesterol, LDL / Q000502:physiology*; D004798:Enzymes; D005260:Female; D005487:Foam Cells / Q000473:pathology*; D006706:Homeostasis; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D018709:Statistics, Nonparametric
D018932:Chemokine CCL2; D008078:Cholesterol, LDL; D004798:Enzymes; D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6