Abstract 1339: LOX-1 Ablation Reduces Atherosclerosis
Atherosclerosis is associated with intense oxidative stress and upregulation of LOX-1, a receptor for oxidized low density lipoprotein (ox-LDL). To determine the contribution of LOX-1 expression in atherogenesis, we studied 4 groups of mice, wild-type C57BL/6J, LDLR KO mice, LOX-1 KO mice, and LDLR-LOX-1 double KO mice (n=10 in each group). All animals were fed with high cholesterol diet (4% cholesterol in vegetable oil) for 18 weeks. Extent of atherosclerosis was determined by Sudan IV staining of the entire length of aorta as well as by cross-section analysis of multiple aortic sections. LOX-1 expression (mRNA and protein) was enhanced in the LDLR KO mice (P<0.01 vs. wild-type mice) and absent in the LOX-1 KO and the double KO mice (P<0.001). Atherosclerosis (Sudan IV staining) was minimal in the wild-type and LOX-1 KO mice, but covered 61± 2% of the aorta in the LDLR KO mice, and was markedly less in the LDLR-LOX-1 double KO mice (36±3% double KO mice, P<0.001 vs. LDLR KO mice). Luminal obstruction, intima-media thickness, and macrophage accumulation, which were abundant in the LDLR KO mice, were dramatically reduced in the double KO mice (P<0.001 vs. LDLR KO mice). Expression of P67 phox NADPH oxidase (marker of oxidant stress) and CD68 (marker of inflammation) was enhanced in the LDLR KO mice (vs. wild-type mice), but not in the double KO mice (P<0.01 vs. LDLR KO mice). On the other hand, the expression of the anti-inflammatory cytokine IL-10 was elevated in the double KO mice (P<0.01 vs. LDLR KO mice). These data demonstrate the significance of LOX-1 over-expression in atherogenesis, which appears to participate by inducing oxidant stress and inflammation.