title: Cellular repressor of E1A-stimulated genes inhibits inflammation to decrease atherosclerosis in ApoE(-/-) mice.
abstract: OBJECTIVE
  Macrophage 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.
  
  
  RESULTS
  Immunostaining 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.
  
  
  CONCLUSIONS
  CREG inhibits inflammation and promotes autophagy mediated by lysosome formation; it might be a potential therapeutic target in atherosclerosis.
authors.affiliation: Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China; Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, 83 Wenhua Road, Shenyang 110016, China.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Sun
authors.affiliation: Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, 83 Wenhua Road, Shenyang 110016, China.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Tian
authors.affiliation: Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, 83 Wenhua Road, Shenyang 110016, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, 83 Wenhua Road, Shenyang 110016, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, 83 Wenhua Road, Shenyang 110016, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, 83 Wenhua Road, Shenyang 110016, China.
authors.forename: Guitang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, 83 Wenhua Road, Shenyang 110016, China.
authors.forename: Chengfei
authors.initials: C
authors.lastname: Peng
authors.affiliation: Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, 83 Wenhua Road, Shenyang 110016, China. Electronic address: yanch1029@126.com.
authors.forename: Chenghui
authors.initials: C
authors.lastname: Yan
authors.affiliation: Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, 83 Wenhua Road, Shenyang 110016, China. Electronic address: yalinghan@gmail.com.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Han
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D002401:Cathepsin B / Q000096:biosynthesis; D056668:Cathepsin L / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C485248:Creg protein, mouse; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D056668:Cathepsin L; C534278:Ctsl protein, mouse
keywords: Atherosclerosis; Autophagy; Cellular repressor of E1A-stimulated genes (CREG); Inflammation; Lysosome; Macrophages