title: Tumor necrosis factor-alpha-induced apoptosis of human coronary artery endothelial cells: modulation by the peroxisome proliferator-activated receptor-gamma ligand pioglitazone.
abstract: The cytokine tumor necrosis factor-alpha (TNF-alpha) plays an important role in endothelial injury, which is associated with the release of reactive oxygen species and the induction of apoptosis. We report on our study of TNF-alpha-induced apoptosis in human coronary artery endothelial cells and its modulation by the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand pioglitazone. Treatment of cells with TNF-alpha (40 ng/mL) resulted in apoptosis as measured by DNA laddering and caspase-3 activation. TNF-alpha treatment decreased the expression of antiapoptotic protein Bcl-2 (P <.05 vs control), but not the expression of Fas or FLIP, in human coronary artery endothelial cells. Treatment of cells with TNF-alpha also enhanced lipid peroxidation (P <.01 vs control). Pretreatment of cells with the PPAR-gamma ligand pioglitazone blocked TNF-alpha-mediated apoptosis, caspase-3 activation, expression of Bcl-2, and lipid peroxidation (P <.01 vs TNF-alpha alone). These results indicate that TNF-alpha induces oxidative stress in human coronary artery endothelial cells, resulting in apoptosis through a reduction in Bcl-2 expression and the subsequent activation of caspase-3. The PPAR-gamma ligand pioglitazone modulates lipid peroxidation, alters Bcl-2 expression and caspase-3 activation, and finally reduces apoptosis. The antioxidant and antiapoptotic effects of pioglitazone may be the mechanism by which this agent reduces endothelial injury.
authors.affiliation: Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205-7199, USA.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Chen
authors.forename: Dayuan
authors.initials: D
authors.lastname: Li
authors.forename: Xingjian
authors.initials: X
authors.lastname: Zhang
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000494:pharmacology; D018929:Cell Culture Techniques; D003331:Coronary Vessels / Q000166:cytology* / Q000473:pathology*; D018736:DNA Adducts; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D015227:Lipid Peroxidation; D000077205:Pioglitazone; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018736:DNA Adducts; D007004:Hypoglycemic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000077205:Pioglitazone