title: Thiazolidinediones inhibit apoptosis and heat shock protein 60 expression in human vascular endothelial cells.
abstract: This study evaluated direct effects of peroxisome proliferatoractivated receptor gamma(PPARgamma) agonists, including thiazolidinediones (TZDs), on vascular cell apoptosis and related protein expression to test the hypothesis that these effects are dependent on i) the respective agent's structure and ii) endothelial cells' vascular origin. Exposure (48 h) of human umbilical vein endothelial cells (HUVECs, n=6) to up to 10 microM troglitazone (TRO), rosiglitazone, pioglitazone, and to up to 50 microM RWJ241947=MCC-555 (RWJ) inhibited (p<0.05) apoptosis by 8-25%, whereas 15-deoxy-Delta(12-14)-prostaglandin J(2) (PGJ(2)) triggered (50 microM: + 400%, p<0.05) endothelial cell death versus control (=100%). Moreover, RWJ (50 microM) completely abrogated TNF-alpha(2000 U/ml) and stearic acid (200 microM) induced apoptosis in HUVECs . Similar results were obtained in human adult (saphenous) vein- and aortic endothelial cells, the latter showing no anti-apoptotic response to TRO. In HUVECs, TZDs' anti-apoptotic effects inversely correlated (r=-0.95, p<0.01) with increased (p<0.05) expression of the apoptosis-inhibitor bcl-2, whereas PGJ(2)-induced apoptosis was associated with upregulation of c-myc (+447%) and E2F-1 (+339%). Additionally, TZDs (by 25-39%) and PGJ(2) (-70%) reduced (p<0.05) expression of heat shock protein 60 (hsp60) showing no correlation with apoptosis (r=0.14, n.s.). Modulation of apoptosis by PPARgammaagonists differs in endothelial cells dependent on their vascular origin and the agonists' structure. Thiazolidinediones' ability to reduce both, endothelial apoptosis and hsp60 expression could well add to beneficial vascular effects attributed to these oral antidiabetic drugs.
authors.affiliation: Department Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Artwohl
authors.forename: Thomas
authors.initials: T
authors.lastname: Hölzenbein
authors.forename: Clemens
authors.initials: C
authors.lastname: Fürnsinn
authors.forename: Angelika
authors.initials: A
authors.lastname: Freudenthaler
authors.forename: Nicole
authors.initials: N
authors.lastname: Huttary
authors.forename: Werner Klaus
authors.initials: WK
authors.lastname: Waldhäusl
authors.forename: Sabina M
authors.initials: SM
authors.lastname: Baumgartner-Parzer
mesh_terms: D001011:Aorta / Q000473:pathology; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000096:biosynthesis*; D002839:Chromans / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008024:Ligands; D008858:Microscopy, Phase-Contrast; D008928:Mitochondria / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D018797:Cell Cycle Proteins; D018834:Chaperonin 60; D002839:Chromans; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D000077154:Rosiglitazone; D020169:Caspases; D000077288:Troglitazone; D015230:Prostaglandin D2; D000077205:Pioglitazone