Cellular repressor of E1A-stimulated genes inhibits inflammation to decrease atherosclerosis in ApoE(-/-) mice
Cellular repressor of E1A-stimulated genes inhibits inflammation to decrease atherosclerosis in ApoE(-/-) mice
复制标题
E1A刺激基因的细胞阻遏物抑制炎症，减少ApoE(-/-)小鼠的动脉粥样硬化
DOI：
10.1016/j.yjmcc.2015.07.001
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发表时间：
2015
影响因子：
5
通讯作者：
Han Yaling
中科院分区：
文献类型：
--
作者：
Sun Mingyu;Tian Xiaoxiang;Liu Yanxia;Zhu Nan;Li Yang;Yang Guitang;Peng Chengfei;Yan Chenghui;Han Yaling
目的巨噬细胞炎症反应在动脉粥样硬化的发病机制中起重要作用。我们研究了e1a刺激基因的细胞抑制因子（CREG）在调节TNF-α诱导的巨噬细胞炎症反应中的作用和机制，并探讨CREG是否可能是动脉粥样硬化的治疗靶点。方法和结果免疫组化和免疫印迹法显示，CREG在人冠状动脉粥样硬化组织中表达降低。体内实验表明，高脂饲料喂养的ApoE - / -小鼠补充重组CREG蛋白可减轻主动脉粥样硬化的发展和炎症。在体外，高脂饲料喂养的ApoE−/−小鼠巨噬细胞的CREG水平低于正常饲料喂养的对照小鼠。免疫组化染色和western blotting进一步证实CREG抑制TNF-α诱导的巨噬细胞炎症反应。补充外源性重组CREG蛋白或沉默CREG基因表明，CREG促进了TNF-α处理的巨噬细胞的自噬。使用自噬抑制剂，3-甲基腺嘌呤和巴菲霉素A，发现CREG通过激活自噬来减弱TNF-α诱导的炎症。此外，补充外源CREG蛋白可刺激组织蛋白酶B和组织蛋白酶L的表达和成熟，并诱导溶酶体的形成，而缺乏CREG则可减少溶酶体的形成。结论creg抑制炎症，促进溶酶体形成介导的自噬；它可能是动脉粥样硬化的潜在治疗靶点。
AimsMacrophage inflammation response is important in the pathogenesis of atherosclerosis. We investigated the role and mechanism of cellular repressor of E1A-stimulated genes (CREG) in regulating TNF-α induced inflammation response in macrophages and explore whether CREG might be a therapeutic target for atherosclerosis.Method and resultsImmunostaining and western blotting showed that expression of CREG was reduced in human atherosclerotic coronary artery. In vivo experiments demonstrated that supplementation of recombinant CREG protein to ApoE−/−mice fed with high fat diet alleviated aortic atherosclerosis development and inflammation. In vitro, macrophage from ApoE−/−mice fed with high fat diet had lower level of CREG compared to control mice fed with normal diet. Immunohistochemical staining and western blotting further confirmed that CREG inhibited inflammatory response of macrophages induced by TNF-α. Supplementation of exogenous recombinant CREG protein or CREG gene silencing showed that CREG promoted autophagy in TNF-α treated macrophages. The use of autophagy inhibitors, 3-methyladenine and bafilomycin A, identified that CREG attenuated TNF-α induced inflammation by activate autophagy. In addition, supplementation of exogenous CREG protein stimulated expression and maturity of cathepsin B and cathepsin L and induced lysosome formation, whereas CREG deficiency reduced lysosomal formation.ConclusionCREG inhibits inflammation and promotes autophagy mediated by lysosome formation; it might be a potential therapeutic target in atherosclerosis.