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和缺血性心脏病相关死亡的主要原因 充血性心力衰竭是最常见的住院病症之一。随着衰老伴随着 普遍的危险因素，如糖尿病、慢性阻塞性肺病、肥胖和高血压， 缺血性心脏病是一种与多种病理有关的心脏疾病，例如冠状动脉疾病 动脉硬化和冠状动脉血栓形成。活化蛋白C（APC）首先被鉴定为天然的 抗凝血酶。除了其抗凝活性外，APC 还具有细胞保护作用，例如抗凝血 炎症和抗细胞凋亡。我们发现心脏中的 APC 活性在 缺血再灌注（I/R）和APC受体EPCR在衰老过程中受损。有趣的是， APC 的施用可以稳定 EPCR 免于 I/R 脱落，并增强心脏耐受性 衰老过程中的缺血性损伤。然而，APC 刺激心脏保护的机制仍然不明确。 不清楚。该项目的目的是阐明 APC 的调解机制 针对缺血性损伤的心脏保护作用，并表征心肌梗塞老兵的 APC 信号传导 患者与健康的退伍军人。 AMP 激活蛋白激酶 (AMPK)，心脏保护信号， 在 APC 处理的小鼠心脏中被激活。此外，缺血再灌注诱导的应激激活蛋白激酶 (SAPK/JNK) APC 处理减弱了信号传导。我们假设 APC 可以预防心肌梗死 通过触发关键信号通路来调节底物代谢并减少缺血性损伤 缺血应激下的炎症反应。将解决两个具体目标来检验该假设： (1)表征APC衍生物在再灌注损伤期间心脏炎症反应中的作用 在老化中； (2)确定APC调节葡萄糖代谢和氧化还原的机制 负责缺血心脏炎症反应的稳态。 APC信号可以是 退伍军人患者与健康退伍军人的心肌梗塞受损情况。我们将阐明哪些 APC 的结构域对于其针对 I/R 损伤的心脏保护作用至关重要，这将提供证据 重组APC可用于治疗缺血性心脏病，且无出血风险。 退伍军人健康相关性：缺血性心脏病影响约一百万人 美国人每年最常因缺血性损伤导致心肌损伤。这笔补助金 进行研究以探索 APC 抑制炎症作用的信号传导机制 从而调节心脏对缺血性损伤的反应。研究结果可能会带来新的治疗方法 旨在限制心肌梗死退伍军人患者心脏损伤的策略。