Increased atherosclerotic lesions in LDL receptor deficient mice with hematopoietic nuclear receptor Rev-erbα knock- down.
Increased atherosclerotic lesions in LDL receptor deficient mice with hematopoietic nuclear receptor Rev-erbα knock- down.
复制标题
DOI：
10.1161/jaha.113.000235
复制
发表时间：
2013-08-20
影响因子：
5.4
通讯作者：
Yan D
中科院分区：
文献类型：
--
作者：
Ma H;Zhong W;Jiang Y;Fontaine C;Li S;Fu J;Olkkonen VM;Staels B;Yan D
核受体Rev‐erbα在生物钟计时、脂质代谢、脂肪形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评估。通过shRNA -慢病毒转导，在小鼠造血细胞中敲除核受体Rev‐erbα，然后将其移植到敲除LDL受体的小鼠骨髓中。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%。与对照组小鼠相比，Rev‐erbα敲除骨髓受体的主动脉瓣周围动脉粥样硬化病变显著增加（P<0.01），而血浆胆固醇、磷脂和甘油三酯水平未受影响。在骨髓单核细胞中，Rev‐erbα过表达可降低炎症M1，增加巨噬细胞M2标记物，而Rev‐erbα敲低可增加巨噬细胞炎症表型。此外，用Rev‐erbα配体血红素处理分化型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剂。
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.