Oxidized LDL modulates Bax/Bcl-2 through the lectinlike Ox-LDL receptor-1 in vascular smooth muscle cells.
Oxidized low density lipoprotein (Ox-LDL) induces apoptosis in vascular smooth muscle cells (VSMCs), which may increase atherosclerotic plaque instability. In this study, we examined the molecular mechanisms causing the Ox-LDL-induced apoptosis in VSMCs, especially focusing on the involvement of Bax/Bcl-2 and the lectinlike Ox-LDL receptor-1 (LOX-1). In cultured bovine aortic smooth muscle cells (BASMCs), Ox-LDL at high concentrations (>60 microg/mL) induced cell death as demonstrated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. DNA fragmentation was increased in BASMCs treated with high concentrations of Ox-LDL, indicating that the Ox-LDL-induced cell death in VSMCs was apoptosis. Ox-LDL upregulated LOX-1 expression through phosphorylation of extracellular signal-regulated kinase in BASMCs, and a neutralizing anti-LOX-1 monoclonal antibody, which can block LOX-1-mediated cellular uptake of Ox-LDL, prevented the Ox-LDL-induced apoptosis in BASMCs. This antibody also suppressed the increase in the Bax to Bcl-2 ratio induced by Ox-LDL in BASMCs. Furthermore, LOX-1 expression was well colocalized with Bax expression in the rupture-prone shoulder areas of human atherosclerotic plaques in vivo. LOX-1 may play an important role in Ox-LDL-induced apoptosis in VSMCs by modulating the Bax to Bcl-2 ratio. These molecular mechanisms may be involved in destabilization and rupture of atherosclerotic plaques.
Kataoka
H
H
Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kume
N
N
Miyamoto
S
S
Minami
M
M
Morimoto
M
M
Hayashida
K
K
Hashimoto
N
N
Kita
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D001161:Arteriosclerosis / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D011973:Receptors, LDL / Q000276:immunology / Q000378:metabolism*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
D000911:Antibodies, Monoclonal; C494826:BAX protein, human; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D051028:bcl-2-Associated X Protein; C099252:oxidized low density lipoprotein; D019950:Mitogen-Activated Protein Kinase 1