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.

项目摘要 临床研究报道了老年人手术应激诱导的急性损伤的发生率更高。这 心脏手术后死亡率，动脉粥样硬化，败血症或冠状动脉成形术的年龄在60岁以上的患者 年龄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 导致与动脉粥样硬化相关的血管不耐受的机制不完全 理解以及调节细胞对急性损伤相关的细胞反应的信号传导途径 由手术应激引起的炎症仍然很大未知。动脉粥样硬化的封闭血管 导致ATP耗竭和随后的AMP积累，该AMP激活AMP激活的蛋白激酶 （AMPK），这是细胞应力反应的核心成分，该反应调节氧化代谢对ATP 在压力条件下恢复。 AMPK调节控制氧化应力相关的途径 血管炎症。我们报告说，巨噬细胞迁移的衰老相关减少 抑制因子（MIF）-AMPK信号级联是重要的因素，导致增加 左前冠状动脉的手术连接对活性氧（ROS）的敏感性。 因此，我们假设衰老与血管细胞的能力下降有关 MIF-AMPK信号传导级联反应响应于动脉粥样硬化引起的炎症，从而导致 恶化的血管损伤。我们将在以下特定目的中检验这一假设：AIM 1，定义 与年龄相关的AMPK信号中的MIF受体对血管炎症的氧化作用响应于AMPK信号传导 压力;和AIM 2，评估小分子MIF激动剂改善应力诱导的MIF-AMPK的能力 心血管系统中的激活。通过这种方式，我们试图提高我们对 炎症响应心脏AMPK信号通路的衰老相关改变的机制 通过冠状动脉的手术结扎。此外，我们提出运动和新型药理 旨在改善氧化应激诱导的血管炎症的策略 人口。