title: Up-Regulation of CREG Expression by the Transcription Factor GATA1 Inhibits High Glucose- and High Palmitate-Induced Apoptosis in Human Umbilical Vein Endothelial Cells.
abstract: Endothelial cell (EC) apoptosis plays a vital role in the pathogenesis of atherosclerosis in patients with diabetes mellitus (DM), but the underlying mechanism remains unclear. Cellular repressor of E1A-stimulated genes (CREG) is a novel gene reported to be involved in maintaining the homeostasis of ECs. Therefore, in the present study, we investigated the role of CREG in high glucose/high palmitate-induced EC apoptosis and to decipher the upstream regulatory mechanism underlying the transcriptional regulation of CREG.
  
  
  
  The expression of CREG and the rate of apoptosis were assessed in lower-limb atherosclerotic lesions from patients with type 2 DM (T2DM). Primary human umbilical vein endothelial cells (HUVECs) were isolated and cultured in a high glucose/high palmitate medium (25 mmol/L D-glucose, 0.4 mmol/L palmitate), and the over-expression and knock-down of CREG were performed in HUVECs to determine the role of CREG in EC apoptosis. The upstream regulatory mechanism of CREG was identified using a promoter-binding transcription-factor profiling array, chromatin immunoprecipitation (ChIP) assay and a mutation analysis.
  
  
  
  Compared with normal arteries from non-diabetic patients, reduced CREG expression and increased apoptosis were found in the endothelium of atherosclerotic lesions from patients with T2DM. In vitro treatment of HUVECs with a high glucose/high palmitate medium also resulted in decreased CREG expression and increased apoptosis. Moreover, high glucose/high palmitate induced-HUVEC apoptosis was increased by the knock-down of CREG and rescued by the over-expression of CREG. We also demonstrated that GATA1 was able to bind to the promoter of the human CREG gene. A deletion mutation at -297/-292 in the CREG promoter disrupted GATA1 binding and reduced the activation of CREG transcription by approximately 83.3%. Finally, the overexpression of GATA1 abrogated the high glucose/high palmitate-induced apoptosis in HUVECs.
  
  
  
  The over-expression of CREG inhibits high glucose/high palmitate-induced apoptosis in HUVECs. CREG is transcriptionally upregulated by GATA1. Thus, CREG might be a potential therapeutic target for intervention of vascular complications related to diabetes.
authors.affiliation: Graduate School of Third Military Medical University, Chongqing, China.|Department of Cardiology and Cardiovascular Research Institute, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology and Cardiovascular Research Institute, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Cardiology and Cardiovascular Research Institute, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology and Cardiovascular Research Institute, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Cardiology and Cardiovascular Research Institute, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Meili
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Cardiology and Cardiovascular Research Institute, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cardiology and Cardiovascular Research Institute, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Quanyu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Cardiology and Cardiovascular Research Institute, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Chenghui
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Cardiology and Cardiovascular Research Institute, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Han
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology; D001483:Base Sequence; D003920:Diabetes Mellitus / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019308:Palmitic Acid / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C114068:CREG1 protein, human; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D012097:Repressor Proteins; D019308:Palmitic Acid; D005947:Glucose