Thiazolidinediones inhibit proliferation of microvascular and macrovascular cells by a PPARγ-independent mechanism

Abstract

Aims/hypothesis: This study evaluated the hypothesis that peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ-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 μmol/l rosiglitazone (RSG), RWJ241947 (RWJ), pioglitazone (PIO), troglitazone (TRO), 15-deoxy-Δ12,14-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 G 0/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≈PIO≈RWJ