AIMS/HYPOTHESIS: This study evaluated the hypothesis that peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, including thiazolidinediones (TZDs) and the rexinoid LG100268 (LG), directly affect human vascular cell function (proliferation, cell cycle, protein expression, lactate release) independently of (1) their PPARgamma-activating potential and (2) the cells' vascular origin. METHODS: Human umbilical vein endothelial cells (HUVECs), human adult vein endothelial cells (HAVECs), human retinal endothelial cells (HRECs) and human retinal pericytes (HRPYCs) were incubated (48 h) with 2-50 micromol/l rosiglitazone (RSG), RWJ241947 (RWJ), pioglitazone (PIO), troglitazone (TRO), 15-deoxy-Delta(12,14)-prostaglandin J2 (PGJ2) and LG. Proliferation, cell cycle distribution, protein expression, peroxisome proliferator-activated receptor responsive element (PPRE) transcriptional activity and mitochondrial effects were determined by [3H]thymidine incorporation, FACS analyses, western blots, reporter assays and lactate release respectively. RESULTS: In HUVECs, RSG, RWJ, PIO, TRO, PGJ2 and LG reduced (p<0.01) proliferation (due to a G0/G1 cell cycle arrest) by up to 23%, 36%, 38%, 86%, 99% and 93% respectively. The antiproliferative response was similar in HRPYCs and HAVECs, but was attenuated in HRECs. Whereas p21WAF-1/Cip1 and p27Kip were differently affected in HUVECs, all agents reduced (p<0.05) expression of cyclins (D3, A, E, B), cyclin-dependent kinase-2 and hyperphosphorylated retinoblastoma protein. The rank order of the antiproliferative effects of TZDs in HUVECs (RSG approximately PIO approximately RWJ<TRO) contrasted their PPRE transcriptional activities (TRO<PIO<RSG<RWJ), but correlated with cellular lactate release. Proliferation inhibition and lactate release were mimicked by rotenone (mitochondrial complex I inhibitor). CONCLUSIONS/ INTERPRETATION: In conclusion, this study suggests that the antiproliferative action of the TZDs in vascular cells is independent of their PPARgamma-activating and associated insulin-sensitising potential, but could relate to mitochondrial mechanisms.
AIMS/HYPOTHESIS: This study evaluated the hypothesis that peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, including thiazolidinediones (TZDs) and the rexinoid LG100268 (LG), directly affect human vascular cell function (proliferation, cell cycle, protein expression, lactate release) independently of (1) their PPARgamma-activating potential and (2) the cells' vascular origin. METHODS:Human umbilical vein endothelial cells (HUVECs), human adult vein endothelial cells (HAVECs), human retinal endothelial cells (HRECs) and human retinal pericytes (HRPYCs) were incubated (48 h) with 2-50 micromol/l rosiglitazone (RSG), RWJ241947 (RWJ), pioglitazone (PIO), troglitazone (TRO), 15-deoxy-Delta(12,14)-prostaglandin J2 (PGJ2) and LG. Proliferation, cell cycle distribution, protein expression, peroxisome proliferator-activated receptor responsive element (PPRE) transcriptional activity and mitochondrial effects were determined by [3H]thymidine incorporation, FACS analyses, western blots, reporter assays and lactate release respectively. RESULTS: In HUVECs, RSG, RWJ, PIO, TRO, PGJ2 and LG reduced (p<0.01) proliferation (due to a G0/G1 cell cycle arrest) by up to 23%, 36%, 38%, 86%, 99% and 93% respectively. The antiproliferative response was similar in HRPYCs and HAVECs, but was attenuated in HRECs. Whereas p21WAF-1/Cip1 and p27Kip were differently affected in HUVECs, all agents reduced (p<0.05) expression of cyclins (D3, A, E, B), cyclin-dependent kinase-2 and hyperphosphorylated retinoblastoma protein. The rank order of the antiproliferative effects of TZDs in HUVECs (RSG approximately PIO approximately RWJ<TRO) contrasted their PPRE transcriptional activities (TRO<PIO<RSG<RWJ), but correlated with cellular lactate release. Proliferation inhibition and lactate release were mimicked by rotenone (mitochondrial complex I inhibitor). CONCLUSIONS/ INTERPRETATION: In conclusion, this study suggests that the antiproliferative action of the TZDs in vascular cells is independent of their PPARgamma-activating and associated insulin-sensitising potential, but could relate to mitochondrial mechanisms.
Authors: Barbara Brunmair; Katrin Staniek; Florian Gras; Nicole Scharf; Aleksandra Althaym; Renate Clara; Michael Roden; Erich Gnaiger; Hans Nohl; Werner Waldhäusl; Clemens Fürnsinn Journal: Diabetes Date: 2004-04 Impact factor: 9.461
Authors: Zuzana Tobiasova; Lufeng Zhang; Tai Yi; Linfeng Qin; Thomas D Manes; Sanjay Kulkarni; Marc I Lorber; Frederick C Rodriguez; Je-Min Choi; George Tellides; Jordan S Pober; Ivana Kawikova; Alfred L M Bothwell Journal: Circulation Date: 2011-06-20 Impact factor: 29.690
Authors: P J Simpson-Haidaris; S J Pollock; S Ramon; N Guo; C F Woeller; S E Feldon; R P Phipps Journal: PPAR Res Date: 2010-02-28 Impact factor: 4.964
Authors: Sabina M Baumgartner-Parzer; Ferdinand Rudolf Waldenberger; Angelika Freudenthaler; Amandine Ginouvès-Guerdoux; David McGahie; Hugues Gatto Journal: ISRN Vet Sci Date: 2012-11-26