Activated Protein C in Acute Injury

急性损伤中的活化蛋白 C

• 批准号: 10475352
• 负责人: Ji Li
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475352
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Acute; Address; Affect; Aging; American; Animals; Anti-Inflammatory Agents; Anticoagulants; Apoptosis; Apoptotic; Attenuated; Brain Infarction; Cardiac; Cardiovascular Diseases; Cause of Death; Cell Survival; Cells; Chronic Obstructive Pulmonary Disease; Clinical; Congestive Heart Failure; Coronary Arteriosclerosis; Coronary Thrombosis; Cytoprotection; Data; Diabetes Mellitus; Diagnostic; Down-Regulation; Enzymes; Extracellular Signal Regulated Kinases; F2R gene; Financial Hardship; Glucose; Goals; Grant; Health; Heart; Heart Injuries; Hemorrhage; Histologic; Homeostasis; Hospitalization; Hypertension; Immunofluorescence Immunologic; Impairment; In Situ Nick-End Labeling; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Ischemic Stroke; JUN gene; Knock-in Mouse; Link; Measures; Mediating; Mental disorders; Metabolic; Metabolism; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; N-terminal; Obesity; Oleates; Oxidation-Reduction; Pathology; Patients; Peptide Hydrolases; Perfusion; Pharmacotherapy; Plasma Proteins; Play; Point Mutation; Population; Prevention; Production; Protein C; Protein Kinase; Proteins; Receptor Activation; Recombinants; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Risk; Risk Factors; Role; SAPK; Signal Pathway; Signal Transduction; Signaling Protein; Stains; Stress; Study Subject; System; TP53 gene; Testing; Transgenic Mice; Veterans; Western Blotting; Work; activated Protein C; activated protein C receptor; age related; blood glucose regulation; cardioprotection; fatty acid metabolism; glucose metabolism; glucose transport; glucose uptake; heart damage; human subject; inflammatory modulation; ischemic injury; military veteran; monocyte; mortality; myocardial damage; myocardial infarct sizing; neutrophil; novel; novel therapeutic intervention; novel therapeutics; prevent; prognostic; protective effect; response; stress activated protein kinase; trafficking

Cardiovascular disease is the leading cause of death among Veterans and ischemic heart disease-related congestive heart failure is among the most common conditions for hospitalization. With aging along with prevalent risk factors such as diabetes, chronic obstructive pulmonary disease, obesity, and hypertension, ischemic heart disease is a cardiac malady that is linked to a variety of pathologies, such as coronary arteriosclerosis and coronary thrombosis. 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. We revealed that APC activity was decreased in the heart during ischemia and reperfusion (I/R), and APC receptor EPCR was impaired in aging. Intriguingly, administration of APC can stabilize EPCR from shedding by I/R and strengthen cardiac tolerance to ischemic insults in aging. 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, and characterize the APC signaling in myocardial infarct veteran patients versus healthy veterans. AMP-activated protein kinase (AMPK), cardioprotective signaling, was activated in APC treated mouse heart. Moreover, I/R-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. Two specific aims will be addressed to test the hypothesis: (1) to characterize the role of APC derivatives in cardiac inflammatory response during reperfusion injury in aging; (2) to determine the mechanisms by which APC modulates glucose metabolism and redox homeostasis that responsible for the inflammatory response in the ischemic heart. APC signaling could be impaired in myocardial infarction Veteran patients versus healthy Veterans. We will elucidate which domains of APC is critical for its cardioprotection against I/R injury, which will provide evidence that recombinant APC can be used for therapy of ischemic heart disease without the risk of bleeding. VETERANS HEALTH RELEVANCE: Ischemic heart disease, which affects approximately one million Americans each year, is most often caused by ischemic insults leading to myocardial damage. This grant pursues studies to explore the signaling mechanisms underlying APC’s role in inhibiting inflammation thereby modulating the heart’s response to ischemic insults. The results could lead to novel therapeutic strategies aimed at limiting cardiac damage for myocardial infarction Veteran patients.

心血管疾病是退伍军人死亡的主要原因，与缺血性心脏病相关 充血性心力衰竭是最常见的住院条件之一。随着年龄的增长 流行的危险因素，如糖尿病、慢性阻塞性肺疾病、肥胖和高血压， 缺血性心脏病是一种心脏疾病，与多种病理因素有关，如冠状动脉 动脉硬化和冠状动脉血栓形成。活化蛋白C(APC)最早被鉴定为一种天然的 抗凝血酶。APC除了具有抗凝血活性外，还具有细胞保护作用，如抗 发炎和抗细胞凋亡。我们发现，心脏中的APC活性在 缺血再灌流(I/R)，APC受体EPCR随增龄而受损。有趣的是， 应用APC可稳定I/R引起的外周血细胞增殖反应，增强心脏耐受性 衰老中的缺血性侮辱。然而，APC刺激心脏保护的机制仍然是 不清楚。本项目的目的是阐明APC调解的机制 心肌梗死退伍军人的心肌保护作用及其APC信号特征 病人和健康的退伍军人。AMP激活的蛋白激酶(AMPK)是心脏保护信号。 在APC处理的小鼠心脏中激活。此外，I/R诱导的应激激活蛋白激酶(SAPK/JNK) APC处理使信号转导减弱。我们假设APC对心肌梗塞有保护作用 通过触发关键信号通路调节底物代谢和减少 缺血应激下的炎症反应。为了检验这一假说，我们将提出两个具体目标： (1)研究APC衍生物在再灌注损伤时心脏炎症反应中的作用 (2)确定APC调节葡萄糖代谢和氧化还原的机制 导致缺血心脏炎症反应的动态平衡。APC信令可以是 心肌梗死退伍军人与健康退伍军人相比，心肌梗死患者的功能受损。我们将澄清哪些是 APC的结构域对于其抗I/R损伤的心脏保护至关重要，这将提供证据 重组APC可用于无出血风险的缺血性心脏病的治疗。 退伍军人健康相关性：影响约100万人的缺血性心脏病 美国人每年，最常见的是由缺血侮辱导致的心肌损伤。这笔赠款 进行研究以探索APC抑制炎症作用的信号机制 从而调节心脏对缺血侮辱的反应。这一结果可能会带来新的治疗方法 旨在限制退伍军人心肌梗死患者心脏损害的策略。