EGF receptor-dependent JNK activation is involved in arsenite-induced p21Cip1/Waf1 upregulation and endothelial apoptosis.
EGF receptor-dependent JNK activation is involved in arsenite-induced p21Cip1/Waf1 upregulation and endothelial apoptosis.
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DOI：
10.1152/ajpheart.00901.2004
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发表时间：
2005-07
期刊：
影响因子：
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通讯作者：
N. Nuntharatanapong;Kai Chen;P. Sinhaseni;J. Keaney
中科院分区：
文献类型：
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作者：
N. Nuntharatanapong;Kai Chen;P. Sinhaseni;J. Keaney
砷暴露会增加动脉粥样硬化和血管疾病的风险。尽管血管内皮细胞长期以来一直被认为是砷中毒的主要靶点，但其潜在的分子机制在很大程度上仍不清楚。在这项研究中，我们试图探索亚砷酸钠触发的信号通路及其对内皮表型的影响。我们发现亚砷酸钠对人脐静脉内皮细胞活力产生时间和剂量依赖性的降低。这种作用与p21Cip1/Waf1(高达10倍)的诱导有关，p21Cip1/Waf1是细胞周期和细胞凋亡的调节蛋白。我们还发现，亚砷酸盐刺激的EGF(ErbB1)和ErbB2受体反式激活，表现为受体酪氨酸磷酸化，似乎是导致p21Cip1/Waf1诱导的近端信号事件，因为药物抑制剂和通过RNA干扰敲除受体都阻断了亚砷酸盐诱导的p21Cip1/Waf1上调。亚砷酸盐诱导的JNK和p38MAPK活化明显，只有JNK是EGF受体的下游靶点。此外，SP-600125或显性阴性MKK7抑制JNK仅抑制p21Cip1/Waf1的诱导，而p38MAPK抑制剂SB-203580或显性阴性MKK4抑制p21Cip1/Waf1和P53的诱导。在功能上，抑制p21Cip1/Waf1诱导可阻止亚砷酸盐诱导的内皮细胞凋亡。就内皮功能障碍促进血管疾病而言，这些数据提供了因接触亚砷酸盐而增加心血管疾病发病率的机制。
Arsenic exposure is associated with an increased risk of atherosclerosis and vascular diseases. Although endothelial cells have long been considered to be the primary targets of arsenic toxicity, the underlying molecular mechanism remains largely unknown. In this study, we sought to explore the signaling pathway triggered by sodium arsenite and its implication for endothelial phenotype. We found that sodium arsenite produced time- and dose-dependent decreases in human umbilical vein endothelial cell viability. This effect correlated with the induction of p21Cip1/Waf1 (up to 10-fold), a regulatory protein of cell cycle and apoptosis. We also found that arsenite-stimulated EGF (ErbB1) and ErbB2 receptor transactivation, manifest as receptor tyrosine phosphorylation, appeared to be a proximal signaling event leading to p21Cip1/Waf1 induction, because both pharmacological inhibitors and knockdown of receptors by RNA interference blocked arsenite-induced p21Cip1/Waf1 upregulation. Arsenite-induced activation of JNK and p38 MAPK was distinct, with only JNK as a downstream target of the EGF receptor. Moreover, inhibition of JNK with SP-600125 or dominant negative MKK7 inhibited only p21Cip1/Waf1 induction, whereas the p38 MAPK inhibitor SB-203580 or dominant negative MKK4 inhibited both p21Cip1/Waf1 and p53 induction. Functionally, inhibition of p21Cip1/Waf1 induction prevented endothelial apoptosis due to arsenite treatment. Insofar as endothelial dysfunction promotes vascular disease, these data provide a mechanism for the increased incidence of cardiovascular disease due to arsenite exposure.