MIF and Cardiovascular Inflammation

MIF 与心血管炎症

• 批准号: 10269328
• 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/10269328
• 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.

项目概要 临床研究表明，老年人手术应激引起的急性损伤发生率较高。这 60 岁以上患者心脏手术、动脉粥样硬化、败血症或冠状动脉成形术后的死亡率 年龄的增长似乎与对手术应激相关急性损伤的内在抵抗力下降有关。这 衰老过程中动脉粥样硬化相关血管不耐受的机制尚不完全 了解并参与调节细胞对急性损伤相关反应的信号通路 手术应激引起的炎症在很大程度上仍然未知。动脉粥样硬化血栓堵塞的血管 导致 ATP 耗尽和随后的 AMP 积累，从而激活 AMP 激活的蛋白激酶 (AMPK)，细胞应激反应的核心成分，调节 ATP 的氧化代谢 应激条件下的恢复。 AMPK 调节控制氧化应激相关通路 血管炎症。我们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 通过手术结扎左冠状动脉前降支对活性氧（ROS）的敏感性。 因此，我们假设衰老与血管细胞提供血管的能力下降有关。 MIF-AMPK 信号级联反应对动脉粥样硬化引起的炎症反应活跃，从而导致 加剧血管损伤。我们将在以下具体目标中检验这一假设： 目标 1，定义 年龄相关的 AMPK 信号受损中的 MIF 受体，通过氧化作用响应血管炎症 压力;目标 2，评估小分子 MIF 激动剂改善应激诱导的 MIF-AMPK 的能力 心血管系统的激活。通过这种方式，我们力求加深对 心脏 AMPK 信号通路响应炎症的衰老相关变化背后的机制 通过手术结扎冠状动脉。此外，我们提出了锻炼和一种新的药理学 旨在改善老年人发生的氧化应激诱导的血管炎症的策略 人口。