title: Aldose reductase regulates TNF-alpha-induced cell signaling and apoptosis in vascular endothelial cells.
abstract: In this study, we examined the role of aldose reductase (AR) in regulating the cytotoxic effects of TNF-alpha on human umbilical vein endothelial cells. Inhibition of AR by sorbinil or tolrestat prevented TNF-alpha-induced increase in Bax and Bak and the downregulation of Bcl-2. Inhibition of AR abrogated AP-1 DNA binding activity and prevented the activation of caspase-3, JNK, and p38 MAPK in cells stimulated by TNF-alpha. Exposure to TNF-alpha also induced apoptotic cell death, which was attenuated by AR inhibition or antisense ablation. These observations suggest that AR is a critical regulator of TNF-alpha-induced apoptotic signaling in endothelial cells.
authors.affiliation: Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, 619 Basic Science Building, Galveston, TX 77555, USA.
authors.forename: Kota V
authors.initials: KV
authors.lastname: Ramana
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Satish K
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000449:Aldehyde Reductase / Q000737:chemistry* / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; D007093:Imidazoles; D048289:Imidazolidines; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D000449:Aldehyde Reductase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C026411:sorbinil