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

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.

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。

项目背景. 肺动脉高压(PAH)是一类以肺动脉重构为特征的进展性疾病。流行病学资料显示PAH在发病率、诊断和预后方面均存在性别差异，女性患者的发病率高于男性；男性患者的病死率高于女性患者，这表明性激素在PAH发病过程中发挥重要作用。既往研究显示雌二醇（E2）对PAH患者及动物模型存在争议作用。申请人前期研究提示PAH大鼠血浆中E2浓度下降，补充E2可抑制PASMCs增殖，然而却促进正常大鼠PASMCs增殖，这一矛盾的机制尚不清楚。.主要研究内容. 通过临床和基础研究明确E2 调节 PAH的作用。在动物模型和细胞模型的实验中阐明E2通过 miR-21及其靶蛋白Arhgap24调节RhoA/Rock活性或表达来调控MCT-PAH大鼠和正常大鼠 PASMCs增殖差异效应的分子机制。此外，探索是否存在其他miRNAs及靶蛋白信号通过参与E2 缓解PAH的作用。.重要结果、关键数据及临床意义. 在本项目研究的过程中我们发现E2对MCT-PAH动物模型的发病及治疗有很大影响，而且通过实验证实E2可能是通过miR-21-5p/Arhgap24/RhoA/Rock和miR-223-3p/IGF-1R信号途经调节 PASMCs增殖的差异效应以及缓解MCT诱导的 PAH 大鼠肺动脉重构。因此，我们明确了miRNA介导雌二醇调控肺动脉平滑肌细胞增殖来调节PAH肺动脉重构机制。该研究不仅能够揭开雌二醇调控PAH肺动脉重构的某种机制，也为肺动脉高压的靶点治疗提供新的思路。.此外，针对临床患者是否受雌激素影响，我们观察了部分特发性肺动脉高压和慢性血栓栓塞性肺动脉高压患者的心肺功能的性别差异，发现心肺运动试验显示的大量心肺功能指标存在显著的性别差异，这可能也提示了雌激素参与了发病过程。随后我们确定了PAH男性患者血浆中E2水平显著升高，并是判断疾病发生和预后差的良好指标；以上结果为我们重新认识性激素在PAH中的作用提供新的思路，为PAH的发病机制和疾病进展中的性别相关的矛盾问题提供新的探索依据。

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