Aims/hypothesis  

This study evaluated the hypothesis that peroxisome proliferator-activated receptor- (PPAR) 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 PPAR-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 mol/l rosiglitazone (RSG), RWJ241947 (RWJ), pioglitazone (PIO), troglitazone (TRO), 15-deoxy-^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 p21^WAF-1/Cip1 and p27^Kip 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 (RSGPIORWJ<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 PPAR-activating and associated insulin-sensitising potential, but could relate to mitochondrial mechanisms.