内源性腺苷及腺苷受体在芍药苷抗脓毒性心功能障碍中的作用研究

Septic shock is the leading cause of death in patients in intensive care unit. About 50% of patients with septic shock experience cardiac dysfunction that is characterized with ventricular expansion and reduced ejection fraction, which influences the prognosis. Therefore, prevention of septic cardiac dysfunction plays an important role in reducing the mortality during sepsis. In our previous study, it is found that paeoniflorin (Pae) significantly reduced the mortality of mice with endotoxemia and cecum ligation and puncture (CLP)-induced sepsis and improved lipopolysaccharide (LPS)-induced cardiac dysfunction. However, the target of the Pae protection effect against septic cardiac dysfunction is still unclear. Some research has shown activating adenosine receptor can antagonize myocardial damage induced by ischemia, while Pae can activate adenosine receptor. Therefore, we hypothesized that Pae may protect against septic cardiac dysfunction through stimulating release of endogenous adenosine and activating adenosine receptor and then inhibiting production of inflammatory factors and apoptosis of cadiomyocyte. For testing the hypothesis, this study will utilize the animal model of sepsis through CLP and cultural cadiomyocytes to examine that the role of endogenous adenosine and adenosine receptor in the protection of Pae against septic cardiac dysfunction and associated mechanism of signal transduction, which has great significance of finding out a new target and strategy for the clinical treatment of septic cardiac function.

脓毒症休克是危重患者死亡的主要原因，约50%的脓毒症休克患者发生以心室扩张、射血分数降低为特征的心功能不全，在很大程度上影响患者预后。因此，如何防止脓毒症性心功能不全的发生对降低脓毒症患者的死亡率具有重大意义。我们前期研究发现芍药苷能显著降低内毒素血症和盲肠结扎穿孔小鼠的死亡率，并减轻内毒素血症小鼠的心功能障碍，然而其发挥抗内毒素性心功能障碍的作用靶点尚不清楚。有研究表明腺苷受体活化可对抗缺血性心肌损伤，而芍药苷能刺激内源性腺苷释放激活腺苷受体，因此我们推测芍药苷可能通过刺激心肌内源性腺苷释放激活心肌腺苷受体，抑制炎症因子表达及心肌细胞凋亡，从而发挥其抗脓毒性心功能障碍作用。为验证上述假说，本项目利用盲肠结扎穿孔小鼠脓毒症模型和培养心肌细胞，观察内源性腺苷及腺苷受体在芍药苷发挥抗脓毒症性心功能障碍中的作用及其相关信号转导机制，对寻找防治脓毒症性心功能障碍的新靶点和治疗策略，具有重要意义。