Increased atherosclerotic lesions in LDL receptor deficient mice with hematopoietic nuclear receptor Rev-erbα knock- down.

Nuclear receptor rev-erbα plays important roles in circadian clock timing,lipid metabolism,adipogenesis,and vascular inflammation. however,the role of rev-erbα in atherosclerotic lesion development has not been assessed in vivo. the nuclear receptor rev-erbα was knocked down in mouse haematopoietic cells by means of shrna-lentiviral transduction,followed by bone marrow transplantation into ldl receptor knockout mice. the rev-erbα protein in peripheral macrophage was reduced by 70% as compared to control mice injected with nontargeting shrna lentivirus-transduced bone marrow. a significant increase in atherosclerotic lesions was observed around the aorta valves as well as upon en face aorta analysis of rev-erbα knock-down bone marrow recipients (p<0.01) as compared to the control mice,while plasma cholesterol,phospholipid,and triacylglycerol levels were not affected. overexpression of rev-erbα in bone marrow mononuclear cells decreased inflammatory m1 while increasing m2 macrophage markers,while rev-erbα knock down increased the macrophage inflammatory phenotype in vitro and in vivo. furthermore,treatment of differentiating macrophages with the rev-erbα ligand heme promoted expression of antiinflammatory m2 markers. these observations identify hematopoietic cell rev-erbα as a new modulator of atherogenesis in mice.