Transcriptional Down-Regulation of Thromboxane A2 Receptor Expression via Activation of MAPK ERK1/2, p38/NF-κB Pathways
Transcriptional Down-Regulation of Thromboxane A2 Receptor Expression via Activation of MAPK ERK1/2, p38/NF-κB Pathways
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DOI：
10.1159/000153247
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发表时间：
2008-09
影响因子：
1.7
通讯作者：
Wei Zhang;Yaping Zhang;L. Edvinsson;Cang-bao Xu
中科院分区：
文献类型：
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作者：
Wei Zhang;Yaping Zhang;L. Edvinsson;Cang-bao Xu
背景资料：我们通过大鼠肠系膜动脉器官培养建立了一种体外模型，以模拟心血管疾病中血管平滑肌细胞（VSMC）受体的变化。利用该模型研究了VSMC血栓素A2（TP）受体的变化。方法和结果：采用离体培养的大鼠主动脉，应用肌层造影、实时荧光定量PCR和免疫组织化学方法，对血管平滑肌细胞TP受体进行研究。我们观察到，器官培养24和48小时导致抑郁症TP受体介导的收缩VSMC，在平行减少TP受体mRNA和蛋白质的表达。Western blot检测细胞外信号调节激酶1和2（ERK 1/2）、p38和核因子-κB（NF-κB）的磷酸化。抑制ERK 1/2、p38或NF-κB可逆转收缩抑制以及受体mRNA表达降低。放线菌素D废除减少TP受体介导的收缩，而抑制翻译，环氧合酶或一氧化氮合酶没有效果。TP受体mRNA的稳定性在器官培养过程中没有变化。结论：本研究首次证实器官培养的大鼠肠系膜动脉通过激活ERK 1/2和p38/NF-κB信号通路下调VSMC TP受体的表达。
Background: We have developed an in vitro model by organ culture of rat mesenteric arteries to imitate vascular smooth muscle cell (VSMC) receptor changes in cardiovascular disease. By using this model, alteration of VSMC thromboxane A2 (TP) receptors was studied. Methods and Results:After organ culture of the arteries, VSMC TP receptors were studied by using myography, real-time PCR and immunohistochemistry. We observed that organ culture for 24 and 48 h resulted in depressed TP receptor-mediated contraction in the VSMC, in parallel with decreased TP receptor mRNA and protein expressions. Phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 and nuclear factor-κB (NF-κB) was seen by Western blot within 1–3 h after organ culture. Inhibition of ERK1/2, p38 or NF-κB reversed depressed contraction as well as decreased receptor mRNA expression. Actinomycin D abolished decreased TP receptor-mediated contraction, while inhibition of translation, cyclooxygenase or nitric oxide synthase had no effect. TP receptor mRNA stability was unchanged during organ culture. Conclusions:The present study has demonstrated for the first time that organ culture of rat mesenteric arteries down-regulates VSMC TP receptor expression through activation of ERK1/2 and p38/NF-κB signal pathways.