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首页> 外文期刊>American Journal of Physiology >EGF receptor-dependent JNK activation is involved in arsenite-induced p21Cip1/Waf1 upregulation and endothelial apoptosis.
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EGF receptor-dependent JNK activation is involved in arsenite-induced p21Cip1/Waf1 upregulation and endothelial apoptosis.

机译：EGF受体依赖的JNK激活参与砷诱导的p21Cip1 / Waf1上调和内皮细胞凋亡。

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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.
机译：砷暴露与动脉粥样硬化和血管疾病的风险增加有关。尽管长期以来一直认为内皮细胞是砷毒性的主要靶标，但其潜在的分子机制仍然很大程度上未知。在这项研究中，我们试图探索由亚砷酸钠触发的信号传导途径及其对内皮表型的影响。我们发现亚砷酸钠在人脐静脉内皮细胞活力中产生时间和剂量依赖性的下降。这种作用与诱导p21Cip1 / Waf1（最多10倍）有关，后者是细胞周期和凋亡的调节蛋白。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，因为这两种药理抑制剂和RNA干扰引起的受体敲除均阻断了亚砷酸盐-诱导p21Cip1 / Waf1上调。砷诱导的JNK和p38 MAPK激活是不同的，只有JNK作为EGF受体的下游靶标。此外，用SP-600125或显性阴性MKK7抑制JNK仅抑制p21Cip1 / Waf1诱导，而p38 MAPK抑制剂SB-203580或显性阴性MKK4抑制p21Cip1 / Waf1和p53诱导。在功能上，抑制p21Cip1 / Waf1诱导可防止由于亚砷酸盐处理而引起的内皮细胞凋亡。就内皮功能障碍促进血管疾病而言，这些数据提供了一种由于砷暴露导致心血管疾病发生率增加的机制。

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