CaSR调节休克血管反应性的作用及与NFAT/miR-1、ATF/miR-208a共调控网络的关系

Vascular hyporeactivity exists in many critical conditions such as severe trauma and shock, which severely restricts the treatment of these diseases. It is of significance to further elucidate the mechanism for probing the effective therapeutic measures. The recently studies in our laboratory found that calcium sensing receptor (CaSR), a specific receptor in response to Ca2+ which play an essential role in vascular smooth muscle contraction, participated in the incidence of vascular hyporesponsiveness after shock, but the mechanism was unkown. Our recent study showed that the gap junction channel protein connexin43 (Cx43) and connexin 40 (Cx40) played an important role in the regulation of the vascular reactivity after hemorrhagic shock. Based on the literature and our pre-experiment’s findings, we hypothesize that CaSR may take part in the occurrence of shock-induced vascular hyporeactivity via regulating Cx43/Cx40 expression ratio. To test this hypothesis, we adopted the hemorrhagic shock rats and co-cultured cells model, to investigate the role of CaSR regulation of Cx43/Cx40 expression ratio in shock-induced vascular hyporeactivity and its relationship to transcription factor-microRNA (NFAT/miR-1, ATF/miR-208a) networks. The main objective tends to explore the new mechanism to explain the occurrence of vascular hyporeactivity, and provide the novel therapeutic targets for clinical critical conditions such as severe trauma and shock.

严重创伤/休克等临床重症存在血管低反应性，它严重制约休克等重症的治疗，深入研究其发生机制具有重要意义。本实验室近期研究发现，血管平滑肌舒缩调节的关键分子——钙离子的特异性受体——钙敏感受体（CaSR）在休克血管反应性调节中具有重要作用，但机制不清。申请者前一项自然基金研究发现，缝隙连接蛋白Cx43和Cx40的表达改变参与休克血管反应性的调节，根据文献分析及本实验室预实验结果，我们推测CaSR可能通过改变Cx43/Cx40表达比例来调节休克后血管反应性。据此，本研究拟采用失血性休克模型和双室共培养细胞模型，研究CaSR是否通过NFAT/miR-1、ATF/miR-208a共调控网络来调节Cx43/Cx40表达比例、进而影响缝隙连接通道功能、参与休克血管反应性的调节，希望探讨休克血管低反应性发生的新机制，为休克等重症的治疗提供新的靶点。

严重创伤休克是导致患者死亡的重要原因。休克后心血管功能障碍、特别是血管低反应性是制约休克救治的重要因素，深入研究其发生机制具有重要意义。本项目围绕血管舒缩功能调节的关键分子——钙敏感受体（CaSR）在创伤休克血管反应性调节中的作用及机制进行了研究。结果发现，CaSR在休克血管反应性调节中具有重要作用，其抑制剂具有明显的抗休克作用；CaSR通过调节Cx43/Cx40表达、影响缝隙连接通道功能，参与血管反应性的调节；CaSR可通过miR-1和NFAT3调节Cx43表达，miR-1与NFAT3之间存在相互调节作用，CaSR还可通过miR-208a调节ATF5进而调节Cx40表达；此外，CaSR还可通过抑制PTH水平、上调α1肾上腺素受体，通过调节miR-429和miR-208a，影响MLC磷酸化，参与血管反应性的调节；氧化应激、ERS和细胞器功能障碍也参与CaSR和Cx43调节血管反应性的过程。研究结果提示，CaSR可能成为严重创伤休克等临床重症救治中新的、关键性的治疗靶点，它的抑制剂具有良好的抗休克作用，可能是一种有希望的休克治疗药物。