Increased Atherosclerotic Lesions in LDL Receptor Deficient Mice With Hematopoietic Nuclear Receptor Rev‐erbα Knock‐ Down

BACKGROUND 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. METHODS AND RESULTS 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. CONCLUSIONS These observations identify hematopoietic cell Rev-erbα as a new modulator of atherogenesis in mice.