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

Previous studies demonstrated an important interaction between nuclear factor-kappaB (NF-kappaB) activation and homocysteine (Hcy)-induced cytokines expression in endothelial cells and vascular smooth muscle cells. However, the underlying mechanism remains illusive. In this study, we investigated the effects of Hcy on NF-kappaB-mediated sICAM-1, TNF-alpha production and the possible involvement of ERK(1/2)/p38MAPK pathway. The effects of rosiglitazone intervention were also examined. Our results show that Hcy 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-kappaB inhibitor; PD98059, MEK inhibitor; SB203580, p38MAPK specific inhibitor; and staurosporine, PKC inhibitor). Next, we investigated the effect of Hcy on ERK(1/2)/p38MAPK pathway and NF-kappaB activity in HUVECs. The results show that Hcy activated both ERK(1/2)/p38MAPK pathway and NF-kappaB-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 ERK(1/2)/p38MAPK phosphorylation, suggesting that Hcy-induced ERK(1/2)/p38MAPK activation is associated with PKC activity. Our results provide evidence that Hcy-induced NF-kappaB activation was mediated by activation of ERK(1/2)/p38MAPK pathway involving PKC activity. Rosiglitazone reduces the NF-kappaB-mediated sICAM-1 and TNF-alpha production induced by Hcy via inhibition of ERK(1/2)/p38MAPK pathway.