Rosiglitazone attenuates NF-kappaB-dependent ICAM-1 and TNF-alpha production caused by homocysteine via inhibiting ERK1/2/p38MAPK activation.
Rosiglitazone attenuates NF-kappaB-dependent ICAM-1 and TNF-alpha production caused by homocysteine via inhibiting ERK1/2/p38MAPK activation.
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发表时间：
2007
影响因子：
3.1
通讯作者：
Yongping Bai;Yuhui Liu;Jia Chen;T. Song;Y. You;Zhenghui Tang;Yuan‐jian Li;Guogang Zhang
中科院分区：
文献类型：
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作者：
Yongping Bai;Yuhui Liu;Jia Chen;T. Song;Y. You;Zhenghui Tang;Yuan‐jian Li;Guogang Zhang
以往的研究表明，核因子-κ B（NF-κ B）的激活和同型半胱氨酸（Hcy）诱导的细胞因子在内皮细胞和血管平滑肌细胞的表达之间的重要相互作用。然而，根本的机制仍然是虚幻的。本研究探讨了同型半胱氨酸对NF-κ B介导的sICAM-1、TNF-α产生的影响以及ERK（1/2）/p38 MAPK通路的可能参与。罗格列酮干预的效果也进行了检查。我们的研究结果表明，同型半胱氨酸增加培养的人脐静脉内皮细胞（HUVECs）中的sICAM-1和TNF-α的水平在时间和浓度依赖性的方式。罗格列酮和不同抑制剂（PDTC，NF-κ B抑制剂; PD 98059，MEK抑制剂; SB 203580，p38 MAPK特异性抑制剂;和staurosporine，PKC抑制剂）可显著抑制这种作用。接下来，我们研究了Hcy对HUVECs中ERK（1/2）/p38 MAPK通路和NF-κ B活性的影响。结果表明，Hcy激活ERK（1/2）/p38 MAPK通路和NF-κ B-DNA结合活性。罗格列酮以及其他抑制剂（SB 203580、PD 98059和PDTC）可显著抑制这些作用。此外，staurosporine预处理可抑制ERK（1/2）/p38 MAPK磷酸化，提示Hcy诱导的ERK（1/2）/p38 MAPK活化与PKC活性有关。我们的结果为Hcy诱导NF-κ B活化是通过ERK（1/2）/p38 MAPK通路介导的，该通路涉及PKC活性。罗格列酮通过抑制ERK（1/2）/p38 MAPK通路减少Hcy诱导的NF-κ B介导的sICAM-1和TNF-α的产生。
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.