Arhgap24介导雌二醇调节肺动肺动脉平滑肌细胞增殖差异效应的机制

项目名称： Arhgap24介导雌二醇调节肺动肺动脉平滑肌细胞增殖差异效应的机制

项目编号： No.81500040

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 袁平

作者单位： 同济大学

项目金额： 18万元

中文摘要： 肺动脉高压（PAH）在发病率、诊断和预后的性别差异可能与雌激素作用相关，但机制不清楚。申请人新近研究提示雌二醇（E2）抑制PAH大鼠肺动脉平滑肌细胞（PASMC）增殖，却不抑制正常大鼠PASMC增殖，这一现象与E2对PAH患者双刃剑作用相似。为解释这一矛盾现象，申请人开展了相关实验，并发现PAH大鼠PASMC中Arhgap24下调，给予E2可上调其表达。文献报道Arhgap24是GTP酶激活蛋白，可通过负性调节RhoA表达影响细胞增殖。因此推测，PAH大鼠PASMC增殖可能与E2、Arhgap24表达下调及RhoA途径活化紧密关联。为证实这一推测，本项目拟在整体和细胞水平通过系列实验阐析E2上调Arhgap24表达，通过抑制已活化的RhoA途径降低PAH大鼠PASMC增殖；而在正常大鼠不能通过非活化状态的RhoA抑制PASMC增殖的机制，为深入认识性激素影响PAH的作用机制提供新思路。

中文关键词： 肺动脉高压；雌二醇；增殖；Arhgap24

英文摘要： Sex differences in the incidence, diagnosis and prognosis of patients with pulmonary arterial hypertension (PAH), suggests that estrogen play an important role in the pathogenesis of PAH, but the mechanism is not clear. Our recent studies indicated that estradiol (E2) can inhibit proliferation of pulmonary artery smooth muscle cell (PASMC) in rats with PAH, but did not inhibit the proliferation of PASMC in normal rats. This phenomenon is similar to a double-edged sword effect of E2 on patients with PAH. To explain this paradox, the applicant carried out the relevant experiments, and found that the Arhgap24 was down regulated in PASMC with PAH rat. Treatment with E2 can up-regulate it’s expression. Studies reported that Arhgap24 is a GTP enzyme activator protein, and it can influence the expression of cell proliferation through negative regulation of RhoA. Therefore, we hypothesized that proliferation of PASMC in rats with PAH may be closely related to E2, down-regulation of Arhgap24 expression and activation of the RhoA pathway. To prove this hypothesis, the program will explicate the mechanism that E2 up-regulate the expression of Arhgap24, through the activation of RhoA pathway to inhibit the proliferation of PASMC in rats with PAH, while not inhibit the proliferation of PASMC in normal rats because of the non-activated RhoA pathway, which will provide a new idea for further understanding the mechanism of sex hormones in PAH.

英文关键词： pulmonary arterial hypertension; estradiol;proliferation;Arhgap24