Activated Protein C and Cardiac Inflammatory Response

活化蛋白 C 与心脏炎症反应

• 批准号: 10004784
• 负责人: Ji Li
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004784
• 关键词: Activated; Protein; Cardiac; Inflammatory; Response

Abstract Activated protein C (APC) was first identified as a natural anticoagulant enzyme. Besides its anticoagulant 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.

抽象的 活化的蛋白C（APC）首先被鉴定为天然抗凝酶。除了它 抗凝活性，APC发挥细胞保护作用，例如抗炎和抗凋亡。它有 显示APC降低了心脏缺血和再灌注期间的死亡率和凋亡率。 但是，APC刺激的心脏保护涉及的机制尚不清楚。这个目的 项目是为了说明APC介导心脏保护抗缺血性损伤的机制。我们的 初步数据表明，APC的给药减少了缺血期间心肌梗死 再灌注。 AMP激活蛋白激酶（AMPK）是一种心脏保护信号传导，在APC处理中激活 鼠标心。此外，缺血和再灌注诱导的应激激活蛋白激酶（SAPK/JNK）信号传导 通过APC治疗减弱。我们假设APC通过 触发关键的信号通路，以调节底物代谢并减少炎症反应 缺血性压力。将解决三个特定目标以检验假设：1）确定调制 APC衍生物在缺血期间通过APC衍生物和心脏再灌注的AMP激活蛋白激酶信号传导； 2） 确定APC衍生物对缺血期间炎症反应和心脏再灌注的影响； 3）确定APC调节葡萄糖转运的机制，以减少ROS负责 缺血性心脏的炎症反应。 APC可能会降低心脏促炎因子 缺血和再灌注以减少心脏损伤。我们还将弄清楚APC的抗凝域是否为 对于其针对缺血和再灌注损伤的心脏保护并不重要，这将提供证据表明 没有抗凝活性的重组APC可以用于治疗缺血性心脏病而没有风险 出血。