RGC-32 (Response Gene to Complement 32) Deficiency Protects Endothelial Cells From Inflammation and Attenuates Atherosclerosis.
RGC-32 (Response Gene to Complement 32) Deficiency Protects Endothelial Cells From Inflammation and Attenuates Atherosclerosis.
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DOI：
10.1161/atvbaha.117.310656
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发表时间：
2018-04
期刊：
影响因子：
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通讯作者：
Chen SY
中科院分区：
文献类型：
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作者：
Cui XB;Luan JN;Dong K;Chen S;Wang Y;Watford WT;Chen SY
本研究旨在探讨补体反应基因32（RGC-32）在动脉粥样硬化形成中的作用及其机制。RGC-32主要表达于载脂蛋白E缺陷（ApoE−/−）小鼠和人类患者动脉粥样硬化病变的内皮细胞（EC）中。RGC-32缺乏（Rgc 32 −/−）可减轻ApoE−/−小鼠中高脂饮食诱导和自发发生的动脉粥样硬化病变，而不影响血清胆固醇浓度。Rgc 32 −/−似乎减少了巨噬细胞的含量，而不改变胶原蛋白和平滑肌的含量或病变中的巨噬细胞增殖。将野生型（WT）小鼠骨髓移植到致死性照射的Rgc 32 −/−小鼠中并没有改变Rgc 32 −/−引起的病变形成和巨噬细胞蓄积的减少，这表明驻留血管细胞中的RGC-32，而不是巨噬细胞，在动脉粥样硬化形成中起着关键作用。重要的是，Rgc 32 −/−在体内和体外均降低了EC中细胞间粘附分子1（ICAM-1）和血管细胞粘附分子1（VCAM-1）的表达，导致肿瘤坏死因子（TNF）-α诱导的单核细胞-EC相互作用减少。RGC-32介导ICAM-1和VCAM-1表达的机制至少部分是通过核因子（NF）-κB信号通路。RGC-32可直接与NF-κB相互作用，促进NF-κ B核转位，并增强TNF-α诱导的NF-κB与ICAM-1和VCAM-1启动子的结合。RGC-32通过诱导内皮细胞ICAM-1和VCAM-1表达，促进单核细胞-EC相互作用，至少部分通过NF-κB信号通路介导动脉粥样硬化形成。
The objective of this study is to determine the role and underlying mechanisms of response gene to complement 32 (RGC-32) in atherogenesis. RGC-32 was mainly expressed in endothelial cells (ECs) of atherosclerotic lesions in both apolipoprotein E-deficient (ApoE−/−) mice and human patients. RGC-32 deficiency (Rgc32−/−) attenuated the high-fat diet-induced and spontaneously developed atherosclerotic lesions in ApoE−/− mice without affecting serum cholesterol concentration. Rgc32−/− appeared to decrease the macrophage content without altering collagen and smooth muscle contents or lesional macrophage proliferation in the lesions. Transplantation of wild-type (WT) mouse bone marrow to lethally irradiated Rgc32−/− mice did not alter Rgc32−/−-caused reduction of lesion formation and macrophage accumulation, suggesting that RGC-32 in resident vascular cells, but not the macrophages, plays a critical role in the atherogenesis. Of importance, Rgc32−/− decreased the expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in ECs both in vivo and in vitro, resulting in a decrease in tumor necrosis factor (TNF)-α-induced monocyte-EC interaction. Mechanistically, RGC-32 mediated the ICAM-1 and VCAM-1 expression, at least partially, through nuclear factor (NF)-κB signaling pathway. RGC-32 directly interacted with NF-κB and facilitated its nuclear translocation, and enhanced TNF-α-induced NF-κB binding to ICAM-1 and VCAM-1 promoters. RGC-32 mediates atherogenesis by facilitating monocyte-EC interaction via the induction of endothelial ICAM-1 and VCAM-1 expression, at least partially, through NF-κB signaling pathway.