title: High glucose induces human endothelial cell apoptosis through a phosphoinositide 3-kinase-regulated cyclooxygenase-2 pathway.
abstract: OBJECTIVE
  Diabetes mellitus causes endothelial dysfunction. The precise molecular mechanisms by which hyperglycemia causes apoptosis in endothelial cells are not yet well understood. The aim of this study was to explore the role of cyclooxygenase-2 (COX-2) and the possible involvement of phosphoinositide 3-kinase (PI3K) signaling in high glucose (HG)-induced apoptosis in human umbilical vein endothelial cells (HUVECs).
  
  
  RESULTS
  For detection of apoptosis, the morphological Hoechst staining and Annexin V/propidium iodide staining were used. Glucose upregulated COX-2 protein expression, which was associated with the induction of prostaglandin (PG) E2 (PGE2), caspase-3 activity, and apoptosis. Unexpectedly, we found that PI3K inhibitors could suppress COX-2 expression, PGE2 production, caspase-3 activity, and the subsequent apoptosis under HG condition. Glucose-induced activation of PI3K resulted in the downstream effector Akt phosphorylation. PI3K inhibitors effectively attenuated the intracellular reactive oxygen species (ROS) generation and nuclear factor kappaB (NF-kappaB) activation. Blocking the PI3K and Akt activities with the dominant-negative vectors greatly diminished the HG-triggered NF-kappaB activation and COX-2 expression and apoptosis.
  
  
  CONCLUSIONS
  These results suggest that HG, via PI3K/Akt signaling, induces NF-kappaB-related upregulation of COX-2, which in turn triggers the caspase-3 activity that facilitates HUVEC apoptosis. Also, HG may cause ROS generation in HUVECs through a PI3K/Akt-dependent pathway.
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Meei Ling
authors.initials: ML
authors.lastname: Sheu
authors.forename: Feng Ming
authors.initials: FM
authors.lastname: Ho
authors.forename: Rong Sen
authors.initials: RS
authors.lastname: Yang
authors.forename: Kuo Fang
authors.initials: KF
authors.lastname: Chao
authors.forename: Wan Wan
authors.initials: WW
authors.lastname: Lin
authors.forename: Shoei Yn
authors.initials: SY
authors.lastname: Lin-Shiau
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D051546:Cyclooxygenase 2; D003925:Diabetic Angiopathies / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D053148:Caspase 3; D020169:Caspases; D002867:Chromones; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D004791:Enzyme Inhibitors; D005947:Glucose; D008565:Membrane Proteins; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496540:PTGS2 protein, human; C494918:AKT1 protein, human; C505407:CASP3 protein, human