Rosiglitazone attenuates NF-κB-dependent ICAM-1 and TNF-α production caused by homocysteine via inhibiting ERK1/2/p38MAPK activation

Previous studies demonstrated an important interaction between nuclear factor-kappaB (NF-kappa B) activation and homocysteine (Hcy)-induced cytokines expression in enclothelial cells and vascular smooth muscle cells. However, the underlying mechanism remains illusive. In this study, we investigated the effects of Hey on NF-kappa B-mediated sICAM-1, TNF-alpha production and the possible involvement of ERK1/2/p38MAPK pathway. The effects of rosiglitazone intervention were also examined. Our results show that Hey increased the levels of sICAM-1 and TNF-alpha in cultured human umbilical vein endothelial cells (HUVECs) in a time- and concentration-dependent manner. This effect was significantly depressed by rosiglitazone and different inhibitors (PDTC, NF-kappa B inhibitor; PD98059, MEK inhibitor; SB203580, p38MAPK specific inhibitor; and staurosporine, PKC inhibitor). Next, we investigated the effect of Hey on ERK1/2/p38MAPK pathway and NF-kappa B activity in HUVECs. The results show that Hey activated both ERK1/2/p38MAPK pathway and NF-kappa B-DNA-binding activity. These effects were markedly inhibited by rosiglitazone as well as other inhibitors (SB203580, PD98059, and PDTC). Further, the pretreatment of staurosporine abrogated ERK1/2/p38MAPK phosphorylation, suggesting that Hcy-induced ERK1/2/p38MAPK activation is associated with PKC activity. Our results provide evidence that Hey-induced NF-kappa B activation was mediated by activation of ERK1/2/p38MAPK pathway involving PKC activity. Rosiglitazone reduces the NF-kappa B-mediated sICAM-1 and TNF-alpha production induced by Hey via inhibition of ERK1/2/p38MAPK pathway. (c) 2007 Elsevier Inc. All rights reserved.