Rosiglitazone via PPARγ-dependent suppression of oxidative stress attenuates endothelial dysfunction in rats fed homocysteine thiolactone

To explore whether rosiglitazone (RSG), a selective peroxisome proliferator-activated receptor (PPAR) agonist, exerts beneficial effects on endothelial dysfunction induced by homocysteine thiolactone (HTL) and to investigate the potential mechanisms. Incubation of cultured human umbilical vein endothelial cells with HTL (1mM) for 24hrs significantly reduced cell viabilities assayed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, as well as enhanced productions of reactive oxygen species, activation of nuclear factor kappa B, and increased intercellular cell adhesion molecule-1 secretion. Pre-treatment of cells with RSG (0.001-0.1mM), pyrollidine dithiocarbamate (PDTC, 0.1mM) or apocynin (0.1mM) for 1hr reversed these effects induced by HTL. Furthermore, co-incubation with GW9662 (0.01mM) abolished the protective effects of RSG on HTL-treated cells. In ex vivo experiments, exposure of isolated aortic rings from. rats to HTL (1mM) for 1hr dramatically impaired acetylcholine-induced endothelium-dependent relaxation, reduced release of nitric oxide and activity of superoxide dismutase, and increased malondialdehyde content in aortic tissues. Preincubation of aortic rings with RSG (0.1, 0.3, 1mM), PDTC or apocynin normalized the disorders induced by HTL. In vivo analysis indicated that administration of RSG (20mg/kg/d) remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats fed HTL (50mg/kg/d) for 8weeks. RSG improves endothelial functions in rats fed HTL, which is related to PPAR-dependent suppression of oxidative stress.