MIF and Cardiovascular Inflammation

MIF 与心血管炎症

• 批准号: 10450128
• 负责人: Ji Li
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450128
• 关键词: 5' -AMP-activated protein kinase; Acute; Age-Years; Aging; Agonist; Alleles; Anterior; Anterior Descending Coronary Artery; Atherosclerosis; Binding; Blood Vessels; CD44 gene; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cardiovascular system; Cell Respiration; Cells; Cellular Stress Response; Clinical Research; Complex; Coronary artery; Cyclic AMP-Dependent Protein Kinases; Elderly; Embryo; Exercise; Fibroblasts; Genotype; Goals; Heart; Human; Impairment; Incidence; Individual; Inflammation; Inflammatory Response; Injury; Integral Membrane Protein; Intervention; Knockout Mice; Laboratories; Lead; Left; Leukocytes; Ligation; Link; Longevity; Migration Inhibitory Factor; Molecular; Mus; Older Population; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathway interactions; Performance; Pharmacology; Phenols; Physical activity; Physiological; Predisposition; Prevention; Protein Kinase; Protocols documentation; Reactive Oxygen Species; Regulation; Reporting; Resistance; Role; Sepsis; Shock; Signal Pathway; Signal Transduction; Source; Stress; Surgical Injuries; Surgical Shock; System; Testing; Vascular Diseases; Vascular System; Work; age related; aged; atherothrombosis; coronary angioplasty; cytokine; ex vivo perfusion; exercise training; heart damage; improved; in vivo; mortality; novel; novel strategies; novel therapeutic intervention; older patient; population based; prevent; receptor; response; restoration; small molecule; vascular inflammation; vascular injury

Project Summary Clinical studies have reported a higher incidence of surgical stress-induced acute injury in the elderly. The mortality after cardiac surgery, atherosclerosis, sepsis, or coronary angioplasty in patients older than 60 years of age appears to be related to a decline in intrinsic resistance to surgical stress-related acute injury. The mechanisms responsible for the atherosclerosis-related vascular intolerance in aging are incompletely understood and the signaling pathways involved in regulating cellular responses to acute injury related inflammation arising from surgical stress remain largely unknown. The blocked vessels by atherothrombosis cause ATP depletion and subsequent AMP accumulation, which activates AMP-activated protein kinase (AMPK), a central component of the cellular stress response that regulates oxidative metabolism towards ATP restoration under stress conditions. AMPK regulates pathways that control the oxidative stress-related vascular inflammation. We have reported that an aging-related reduction in the macrophage migration inhibitory factor (MIF)-AMPK signaling cascade is an important contributing factor leading to increased sensitivity to reactive oxygen species (ROS) by surgical ligation of the left anterior descending coronary artery. Accordingly, we hypothesize that aging is associated with a decline in the ability of vascular cells to render the MIF-AMPK signaling cascade active in response to inflammation caused by atherosclerosis, thus resulting in exacerbated vascular injury. We will test this hypothesis in the following specific aims: Aim 1, define the role of the MIF receptor in age-related impaired AMPK signaling in response to vascular inflammation by oxidative stress; and Aim 2, evaluate the capability of small-molecule MIF agonist to improve stress-induced MIF-AMPK activation in the cardiovascular system. In this manner, we seek to advance our understanding of the mechanisms behind aging-related alterations in cardiac AMPK signaling pathways in response to inflammation by surgical ligation of the coronary artery. Furthermore, we propose both exercise and a novel pharmacological strategy aimed at ameliorating oxidative stress-induced vascular inflammation that occurs in the older population.

项目摘要 临床研究报告了老年人手术应激引起的急性损伤的发生率较高。的 60岁以上患者心脏手术、动脉粥样硬化、脓毒症或冠状动脉成形术后的死亡率 年龄的增加似乎与对手术应激相关急性损伤的内在抵抗力下降有关。的 老年人动脉粥样硬化相关血管不耐受的机制尚不完全 了解和参与调节细胞对急性损伤相关反应的信号通路 由手术应激引起的炎症仍然在很大程度上未知。动脉粥样硬化血栓形成阻塞的血管 引起ATP耗竭和随后的AMP积累，从而激活AMP活化蛋白激酶 （AMPK），细胞应激反应的中心组分，调节朝向ATP的氧化代谢 应力条件下的恢复。AMPK调节控制氧化应激相关的通路 血管炎症我们已经报道了与衰老相关的巨噬细胞迁移减少 抑制因子（MIF）-AMPK信号级联是导致增加的重要因素 通过手术结扎冠状动脉左前降支，观察对活性氧（ROS）的敏感性。 因此，我们假设衰老与血管细胞使血管再生的能力下降有关。 MIF-AMPK信号级联反应对动脉粥样硬化引起的炎症反应活跃，因此导致 加重了血管损伤我们将在以下具体目标中检验这一假设：目标1，定义 年龄相关性受损AMPK信号转导中的MIF受体对氧化应激引起的血管炎症反应的影响 目的2，评价小分子MIF激动剂改善应激诱导的MIF-AMPK的能力 激活心血管系统。通过这种方式，我们力求增进我们对 炎症反应中心脏AMPK信号通路衰老相关改变的机制 通过外科手术结扎冠状动脉此外，我们提出了运动和一种新的药理学方法， 旨在改善老年人中发生的氧化应激诱导的血管炎症的策略 人口