title: High glucose-induced apoptosis in human coronary artery endothelial cells involves up-regulation of death receptors.
abstract: BACKGROUND
  High glucose can induce apoptosis in vascular endothelial cells, which may contribute to the development of vascular complications in diabetes. We evaluated the role of the death receptor pathway of apoptotic signaling in high glucose-induced apoptosis in human coronary artery endothelial cells (HCAECs).
  
  
  METHODS
  HCAECs were treated with media containing 5.6, 11.1, and 16.7 mM of glucose for 24 h in the presence or absence of tumor necrosis factor (TNF)-α. For detection of apoptosis, DNA fragmentation assay was used. HCAEC expression of death receptors were analyzed by the PCR and flow cytometry methods. Also, using immunohistochemical techniques, coronary expression of death receptors was assessed in streptozotocin-nicotinamide-induced type 2 diabetic mice.
  
  
  RESULTS
  Exposure of HCAECs to high glucose resulted in a significant increase in TNF-R1 and Fas expression, compared with normal glucose. High glucose increased TNF-α production by HCAECs and exogenous TNF-α up-regulated TNF-R1 and Fas expression in HCAECs. High glucose-induced up-regulation of TNF-R1 and Fas expression was undetectable in the presence of TNF-α. Treatment with TNF-R1 neutralizing peptides significantly inhibited high glucose-induced endothelial cell apoptosis. Type 2 diabetic mice displayed appreciable expression of TNF-R1 and Fas in coronary vessels.
  
  
  CONCLUSIONS
  In association with increased TNF-α levels, the death receptors, TNF-R1 and Fas, are up-regulated in HCAECs under high glucose conditions, which could in turn play a role in high glucose-induced endothelial cell apoptosis.
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Kageyama
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kageyama-Yahara
authors.forename: Ryo
authors.initials: R
authors.lastname: Uchimido
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Matsuda
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013311:Streptozocin / Q000009:adverse effects; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D053200:Fas-Associated Death Domain Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D047888:Receptors, Tumor Necrosis Factor, Type I; D013311:Streptozocin; D005947:Glucose