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 smo oth muscle cells (VSMCs), which may increase atherosclerotic plaque instabi lity. In this study, we examined the molecular mechanisms causing the Ox-LD L-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 aor tic smooth muscle cells (BASMCs), Ox-LDL at high concentrations (> 60 mug/m L) induced cell death as demonstrated by the 3-(4,5-dimethylthiazol-2-yl)-2 ,5-diphenyltetrazolium bromide assay. DNA fragmentation was increased in BA SMCs treated with high concentrations of Ox-LDL, indicating that the Ox-LDL -induced cell death in VSMCs was apoptosis. Ox-LDL upregulated LOX-1 expres sion through phosphorylation of extracellular signal-regulated kinase in BA SMCs, and a neutralizing anti-LOX-l monoclonal antibody, which can block LO X-l-mediated cellular uptake of Ox-LDL, prevented the Ox-LDL-induced apopto sis in BASMCs. This antibody also suppressed the increase in the Bar to Bcl -2 ratio induced by Ox-LDL in BASMCs. Furthermore, LOX-I expression was wel l colocalized with Fax expression in the rupture-prone shoulder areas of hu man atherosclerotic plaques in vivo. LOX-I may play an important role in Ox -LDL-induced apoptosis in VSMCs by modulating the Bar to Bcl-2 ratio. These molecular mechanisms may be involved in destabilization and rupture of ath erosclerotic plaques.