Activated Protein C and Cardiac Inflammatory Response

摘要 活化蛋白C（APC）是最早被发现的一种天然抗凝酶。除了它的反- 由于APC具有凝血活性，APC发挥细胞保护作用，如抗炎和抗凋亡。它有 结果表明，APC可降低心肌缺血再灌注过程中的死亡率和凋亡率。 然而，APC刺激心脏保护的机制仍不清楚。的目的 本研究旨在阐明APC介导的心肌保护作用机制。我们 初步数据表明，APC的施用减少了缺血期间的心肌梗死， 再灌注腺苷酸活化蛋白激酶（AMPK），一种心脏保护信号，在APC处理的 老鼠心脏此外，缺血和再灌注诱导的应激激活蛋白激酶（SAPK/JNK）信号转导通路 APC处理可使其减弱。我们假设APC通过以下途径保护心肌缺血损伤： 触发重要的信号传导通路以调节底物代谢并减少炎症反应 缺血性应激。三个具体的目标将被解决来检验假设：1）确定调制 在心脏缺血和再灌注期间，APC衍生物的AMP激活蛋白激酶信号传导; 2） 确定APC衍生物对心脏缺血和再灌注期间炎症反应的影响; 3)确定APC调节葡萄糖转运的机制， 缺血性心脏的炎症反应。APC可降低心肌炎性细胞因子的表达， 缺血和再灌注以减少心脏损伤。我们还将弄清楚APC的抗凝域是否是 对于其抗缺血和再灌注损伤的心脏保护作用并不重要，这将提供证据， 无抗凝活性的重组APC可用于治疗缺血性心脏病而无风险 出血。

Abstract Activated protein C (APC) was first identified as a natural anticoagulant enzyme. Besides its anti- coagulant activity, APC exerts cytoprotective effects such as anti-inflammatory and anti-apoptosis. It has revealed that APC reduces the mortality rate and apoptotic rate during cardiac ischemia and reperfusion. However, the mechanism involved in cardioprotection stimulated by APC is still unclear. The objective of this project is to illustrate the mechanism by which APC mediates cardioprotection against ischemic injury. Our preliminary data demonstrated that the administration of APC reduced myocardial infarction during ischemia and reperfusion. AMP-activated protein kinase (AMPK), a cardioprotective signaling, was activated in APC treated mouse heart. Moreover, ischemia and reperfusion-induced stress-activated protein kinase (SAPK/JNK) signaling was attenuated by APC treatment. We hypothesize that APC protects against myocardial ischemic injury by triggering crucial signaling pathways to modulate substrates metabolism and reducing inflammatory response under ischemic stress. Three specific aims will be addressed to test the hypothesis: 1) determine the modulation of AMP activated protein kinase signaling by APC derivatives during ischemia and reperfusion in the heart; 2) determine the effect of APC derivatives on inflammatory response during ischemia and reperfusion in the heart; 3) determine the mechanisms by which APC modulates glucose transport that reduces ROS responsible inflammatory response in the ischemic heart. APC may decrease the pro-inflammatory factors during cardiac ischemia and reperfusion to reduce heart injury. We also will figure out whether anticoagulant domain of APC is not important for its cardioprotction against ischemia and reperfusion injury, which will provide evidence that recombinant APC without anticoagulant activity can be used for therapy of ischemic heart disease without risk of bleeding.