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.

项目总结