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

Background-Nuclear receptor Rev-erb alpha plays important roles in circadian clock timing, lipid metabolism, adipogenesis, and vascular inflammation. However, the role of Rev-erb alpha in atherosclerotic lesion development has not been assessed in vivo. Methods and Results-The nuclear receptor Rev-erb alpha 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-erb alpha 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-erb alpha 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-erb alpha in bone marrow mononuclear cells decreased inflammatory M1 while increasing M2 macrophage markers, while Rev-erb alpha knock down increased the macrophage inflammatory phenotype in vitro and in vivo. Furthermore, treatment of differentiating macrophages with the Rev-erb alpha ligand heme promoted expression of antiinflammatory M2 markers. Conclusions-These observations identify hematopoietic cell Rev-erb alpha as a new modulator of atherogenesis in mice.