Abstract 877: Oxidized-LDL Receptor-1 (Lox-1) Mediates Macrophage Trafficking Into Aortic Wall In Atherosclerosis
LOX-1, a receptor for oxidized LDL, is expressed on vascular endothelial cells, smooth muscle cells, platelets and macrophages. LOX-1 plays a role in atherogenesis. Our previous study in LOX-1−/− mice revealed that LOX-1 deletion results in a marked reduction in atherogenesis (Circ Res May, 2007). However, the underlying mechanism of the role of LOX-1 in atherogenesis is still unclear. We hypothesized that LOX-1 functions as an adhesion molecule and contributes to atherosclerosis progression by mediating macrophage migration. We studied wild-type (WT), LDLr−/−, LOX-1−/− and LOX-1/LDLr double knock-out (DKO) mice fed high cholesterol diet for 20 weeks, and their aortas were enzymatically digested and accumulation of macrophages and T lymphocytes was analyzed by flow cytometry. Leukocytes were labeled with anti-CD45 and further analyzed by staining with anti-CD3, T cell marker, and anti I-Ab, combined with anti CD11b antibody to detect macrophages. At 8 weeks, there were fewer macrophages in LOX-1−/−compared to WT, 0.16% and 0.45%, respectively, and fewer macrophages in LOX-1/LDLr DKO (0.27%) compared to LDLr−/− mice aortas (1.15%). At 12 weeks, there was significant reduction of macrophages in LOX-1/LDLr DKO as compared to LDLr−/−, 0.74 % (vs. 5.56%). LOX-1−/− mice showed less macrophage trafficking compared to WT, 0.59% (vs. 1.95%). At 20 weeks, there was a reduction of macrophage accumulation in LOX-1/LDLr DKO as compared to LDLr−/− mice (1.6% vs. 2.6%). LOX-1−/− mice showed less macrophage trafficking compared to wild type mice (0.1% vs. 0.2%). Immunohistochemistry with Sudan IV staining and oil red O staining of the aorta confirmed the marked reduction of atherosclerotic lesion size of LOX-1/LDLr DKO compared to LDLR−/− mice. The expression of LOX-1 in macrophages isolated from aorta was confirmed by cell sorting and RT-PCR. Our results suggest that macrophage trafficking into the aorta increases in hypercholesterolemic LDLr−/− mice and LOX-1 plays an important role in mediating this phenomenon. In addition, we found that the accumulation of macrophages increases from week 8 to week 12, but it decreases at week 20. Thus, LOX-1 plays an important role in atherogenesis by mediating macrophage migration into the aortic wall.