Abstract 564: CD146 Deficiency Leads to Accelerated Atherosclerosis in Mice

Abstract

Atherosclerosis is a chronic inflammatory disease of the large vessels and its progression is based in part on the continued recruitment of macrophages in the inflammatory wall. The well described role of CD146 in leukocyte infiltration in vitro suggests a role for this endothelial junction molecule in the early stages of the formation of atherosclerotic plaques. However, the involvement of CD146 in atherogenesis has not been elucidated. To investigate the role of CD146 deficiency in atherosclerosis, CD146 knocked-out (KO) mice were bred with ApoE KO mice. Mice were fed a high-fat Western diet for 24 weeks and were monitored for aortic wall thickness using high frequency ultrasound. After 24 weeks of diet, the arterial wall thickness was significantly higher in CD146 deficient mice (0.19±0.01mm vs 0.27±0.01mm; p=0.012) and there was a significant 47 % increase (p=0.015) in total aortic lesion area, evaluated by histological oil red O coloration. However, mice weights and total cholesterol plasma levels were similar between the two groups of mice. We detected a 2-fold increase in macrophage recruitment to the atherosclerotic plaque of the double KO mice compared with ApoE KO mice, suggesting that the atherosclerotic lesions in these mice were more inflammatory. In addition, CD146 deficient plaques contained significantly less smooth muscle cells (p=0.036) and could be more vulnerable. We observed a maladaptive immune response in double KO mice since the circulating neutrophils and monocytes were significantly increased (p=0.008 and p=0.015 respectively) in the absence of CD146 whereas circulating T lymphocytes were significantly decreased (p=0.026). In a similar way, splenocytes isolated from double KO mice contained significantly lower levels of T cells (p=0.002), suggesting a default of adaptive immunity in the absence of CD146 during atherosclerosis. Our results demonstrated the involvement of CD146 in the progression of atherosclerosis in mice. Our data also suggest that CD146 is involved in the regulation of adaptive immune response and its absence lead to an inflammatory phenotype, which could influence atherosclerosis plaque fate. Thus, CD146 should be considered as a potential target for protection against atherosclerosis.