MIF and Cardiovascular Inflammation

项目摘要 临床研究报告了老年人外科应激所致急性损伤的发生率较高。这个 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 年龄的增加似乎与手术应激相关的急性损伤的内在抵抗力下降有关。这个 动脉粥样硬化相关的血管耐受性在衰老过程中的作用机制不完全 了解和参与调节细胞对急性损伤相关反应的信号通路 手术应激引起的炎症在很大程度上仍不清楚。动脉粥样硬化血栓形成所堵塞的血管 导致ATP耗竭和随后的AMP积聚，从而激活AMP激活的蛋白激酶 (AMPK)，细胞应激反应的中心成分，调节向ATP的氧化代谢 应力条件下的修复。AMPK调控氧化应激相关途径的研究 血管发炎。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信号通路是导致 外科结扎冠状动脉左前降支对活性氧的敏感性。 因此，我们假设衰老与血管细胞呈递血管的能力下降有关 MIF-AMPK信号通路在动脉粥样硬化引起的炎症反应中活跃，从而导致 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 MIF受体在氧化损伤的AMPK信号通路中的作用 目的2、评价小分子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，我们寻求增进我们对 炎症反应中与衰老相关的心脏AMPK信号通路改变的机制 通过外科手术结扎冠状动脉。此外，我们提出了锻炼和一种新的药理作用。 旨在改善老年人氧化应激诱导的血管炎症的策略 人口。

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.