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 活化蛋白C（APC）首先被鉴定为天然抗凝血酶。除了它的 APC具有抗凝血活性，具有抗炎、抗凋亡等细胞保护作用。它有 研究表明，APC 可以降低心脏缺血和再灌注期间的死亡率和细胞凋亡率。 然而，APC 刺激心脏保护的机制仍不清楚。此举的目的 该项目旨在阐明 APC 介导针对缺血性损伤的心脏保护作用的机制。我们的 初步数据表明，施用 APC 可减少缺血期间的心肌梗死，并且 再灌注。 AMP 激活蛋白激酶 (AMPK) 是一种心脏保护信号，在 APC 治疗中被激活 老鼠的心。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 APC 处理可减弱。我们假设 APC 通过以下方式保护心肌免受缺血性损伤： 触发关键信号通路来调节底物代谢并减少炎症反应 在缺血应激下。将解决三个具体目标来检验假设：1）确定调制 心脏缺血和再灌注期间 APC 衍生物对 AMP 激活蛋白激酶信号传导的影响； 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 调节葡萄糖转运以减少 ROS 的机制 缺血性心脏的炎症反应。 APC 可能会减少心脏过程中的促炎因子 缺血和再灌注以减少心脏损伤。我们还将弄清楚APC的抗凝结构域是否是 对于其对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，无风险 出血。