氢分子在妊娠期高血压疾病中对MAPK信号通路的影响

Hypertension disorders in pregnancy (HDCP) is one of the most serious complication during pregnancy, whose pathogenesis remains to be complex. Placental and maternal oxidative stress is one of the most important factors which cause HDCP. The clinical efficacy of routine antioxidants such as Vitamin C and Vitamin E remains to be unsatisfactory, mainly because of the low membrane permeability, high toxicity and restricted therapeutic window. Molecular hydrogen was the new type of selective antioxidant，which has been found in recent years. By establishing the gestational hypertension rat model and cell model in our preliminary studies,we found out that the preventive administration of hydrogen significantly attenuated the severity of HDCP, which might be ascribed to a reduction in inflammation response and oxidative stress. However, its deep mechanism for blocking the pathogenesis requires further investigation. Previous literatures indicated that placenta induced reactive oxygen species (ROS) was thought to be responsible for the activation of mitogen-activated protein kinases (MAPK), followed by a systemic inflammatory reaction to placenta apoptotic or necrotic debris shed to maternal blood and placental-derived factors, giving rise to the endothelial dysfunction and clinical symptoms. Therefore, hydrogen as antioxidants agent, may have effects on the MAPK signaling pathway by blocking ROS, thereby reducing the inflammatory reaction and apoptosis, finally improving the prognosis of HDCP. By employing the previously established gestational hypertension rat model and cell model, this study aimed to investigate the influence of molecular hydrogen on the MAPK signaling pathways from the mRNA and protein levels, and furhter explore the mechanism of hydrogen in the pathogenesis of HDCP by upregulation or supression of the MAPK signaling pathways, respectively.

妊娠期高血压疾病（HDCP）是严重的妊娠合并症之一，发病机制复杂。胎盘和母体的氧化应激（OS）是目前公认的重要发病机制之一，常规抗氧化剂（如Vit C/E）因其通透性差和治疗窗狭窄等因素，临床疗效欠佳。氢分子是近年发现新型选择性抗氧化剂，本研究前期已构建HDCP大鼠和滋养细胞模型，发现氢分子在体内和体外均可降低氧化应激和炎症水平，改善HDCP预后，但其作用机制尚待进一步明确。既往研究发现，HDCP产生的活性氧（ROS）可激活促分裂素原活化蛋白激酶(MAPK)等信号通路，促使炎症介质释放、细胞凋亡，并导致血管内皮功能障碍，提示氢分子可能通过下调ROS从而阻断该信号通路，抑制炎症因子表达和细胞凋亡，最终改善HDCP预后。本研究拟采用前期构建的大鼠和细胞模型，分别从mRNA与蛋白质水平，研究氢分子对MAPK信号通路的影响，并通过上调或抑制MAPK信号通路，探索氢分子改善HDCP预后的深入机制。

妊娠期高血压疾病是导致孕产妇死亡及胎儿死亡和严重并发症的主要原因，其发病机制并未十分明确。近年来，部分学者通过研究发现，由于胎盘子宫螺旋动脉重铸异常，导致胎盘氧化应激水平升高，进而引发母体内皮细胞功能障碍，可能是妊娠期高血压疾病的重要发病机制。传统的抗氧化剂（如维生素C和维生素E等）对妊娠高血压疾病的预防和治疗并不理想，其中可能涉及到常规抗氧化剂对细胞膜的通透性和较窄的安全治疗窗口等问题。在本课题的预实验中我们发现：氢气通过干预妊娠期高血压大鼠模型，显著改善了其妊娠结局、胎盘和肾脏的功能及形态，提示氢气对妊娠期高血压疾病的潜在治疗效果。但是氢气干预妊娠期高血压疾病涉及到的机制及相关信号通路、对母体或胎儿的治疗作用及安全性有待进一步研究。.本课题通过获取人胎盘滋养细胞，建立原代胎盘滋养细胞模型，用不同浓度的含氢培养基对胎盘滋养细胞进行培养，观察氢气对重度子痫前期胎盘滋养细胞的保护作用以及其中涉及到的机制和信号通路，实验结果证实:1.不同浓度的含氢培养基（0umol/L，25umol/L，50umol/L，100umol/L，200umol/L）对人正常妊娠滋养细胞进行培养时，滋养细胞增殖活性无明显差异。2.氢气可降低细胞内P38MAPK、IL-6、caspase-3、Bax-2等相关信号通路蛋白的表达水平，表明氢气可以通过抑制细胞内炎症反应、抑制氧化应激水平及ROS的产生、减少细胞的凋亡、促进重度子痫前期胎盘滋养细胞进行增殖，进而改善重度子痫前期胎盘细胞内病理损伤，从一定程度上延缓妊娠期高血压疾病的进程，为该病的治疗和预防了提供理论依据和可能性。