Department of Biotechnology, Jinan University, Guangzhou, China.
J Am Heart Assoc. 2013 Aug 20;2(4):e000235. doi: 10.1161/JAHA.113.000235.
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.
核受体 Rev-erbα 在生物钟计时、脂质代谢、脂肪生成和血管炎症中发挥重要作用。然而，Rev-erbα 在动脉粥样硬化病变发展中的作用尚未在体内进行评估。
通过 shRNA-慢病毒转导手段在小鼠造血细胞中敲低核受体 Rev-erbα，然后将骨髓移植到 LDL 受体敲除小鼠中。与注射非靶向 shRNA 慢病毒转导骨髓的对照小鼠相比，外周巨噬细胞中的 Rev-erbα 蛋白减少了 70%。与对照小鼠相比，Rev-erbα 敲低骨髓受者的主动脉瓣周围以及主动脉正面分析的动脉粥样硬化病变明显增加（P<0.01），而血浆胆固醇、磷脂和三酰甘油水平不受影响。在骨髓单核细胞中过表达 Rev-erbα 可降低炎症性 M1 标志物，同时增加 M2 巨噬细胞标志物，而 Rev-erbα 敲低可增加体外和体内的巨噬细胞炎症表型。此外，用 Rev-erbα 配体血红素处理分化的巨噬细胞可促进抗炎 M2 标志物的表达。
这些观察结果表明，造血细胞 Rev-erbα 是小鼠动脉粥样硬化形成的一种新的调节因子。
