title: Cellular Repressor of E1A-Stimulated Genes Is a Critical Determinant of Vascular Remodeling in Response to Angiotensin II.
abstract: OBJECTIVE
  Cellular repressor of E1A-stimulated genes (CREG) is a lysosomal glycoprotein implicated in maintaining vascular homeostasis. Here, we have hypothesized that CREG is a critical target of intervention for the prevention of hypertensive vascular remodeling.
  
  
  RESULTS
  CREG gene expression was significantly decreased accompanied by an upregulated expression of angiotensin II (Ang II) in remodeled vascular tissues of high salt-induced Dahl salt-sensitive rats and Ang II-induced mice. In particular, the downregulation of CREG gene was Ang II specific and independent from blood pressure. Prominent medial hypertrophy and vascular fibrosis in both thoracic aortas and mesenteric arteries were observed in CREG+/-mice infused with Ang II than in CREG+/+mice, but blunted response in CREG+/+mice received recombinant human CREG protein, suggesting that changes in CREG expression account for the different phenotype between genotypes. Within a tiled promoter array, E26 transformation-specific-1 binds to CREG promoter at high stringency with the stimulation of Ang II. Moreover, the Ang II-induced E26 transformation-specific-1 directly interacted with the CREG promoter (-1179 and -271 bp) and inhibited its transcription in vascular smooth muscle cells. Selective, pharmacological inhibition of E26 transformation-specific-1 led to restoration of CREG expression in aortas and rescue of experimental vascular remodeling by systemic administration of dominant negative E26 transformation-specific-1 membrane-permeable peptides.
  
  
  CONCLUSIONS
  CREG is a novel mediator of vascular remodeling in response to Ang II and may be an attractive therapeutic target for prevention of vascular diseases.
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Tian
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Haixu
authors.initials: H
authors.lastname: Song
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Meili
authors.initials: M
authors.lastname: Liu
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Haiwei
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Quanyu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Chengfei
authors.initials: C
authors.lastname: Peng
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Chenghui
authors.initials: C
authors.lastname: Yan
authors.affiliation: From the Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China. yalinghan@gmail.com.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Han
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism* / Q000473:pathology; D001794:Blood Pressure; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006984:Hypertrophy; D008638:Mesenteric Arteries / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020303:Rats, Inbred Dahl; D011994:Recombinant Proteins / Q000008:administration & dosage; D012097:Repressor Proteins / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary; D013997:Time Factors; D014162:Transfection; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: C114068:CREG1 protein, human; C485248:Creg protein, mouse; C495367:Creg1 protein, rat; C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D011994:Recombinant Proteins; D012097:Repressor Proteins; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II
keywords: Ang II; CREG; Ets1; VSMCs; vascular remodeling