AMPK-SIRT1 Signaling in the Adaptive Metabolic Response

 描述(由申请人提供)：临床研究报告60岁以上的患者在心肌梗死、冠状动脉成形术或心脏手术后缺血性心脏病的发生率和死亡率较高，这似乎与固有的心肌损伤抵抗力下降有关。与年龄相关的缺血耐受的发生机制尚不完全清楚，参与调节细胞对缺血/再灌注反应的信号通路在很大程度上仍不清楚。我们最近报道，与衰老相关的AMP激活蛋白激酶(AMPK)信号的减少是通过调节葡萄糖转运体(GLUT4)易位而导致对缺血应激敏感性增加的一个重要因素。有趣的是，Sirtuin 1(SIRT1)是一种长寿蛋白质， 成为与心脏病相关的潜在AMPK下游靶点。因此，推测老年心脏中AMPK-SIRT1信号通路受损导致老年人对缺血损伤的耐受性。我们将验证这一假设，以调查SIRT1信号在老年心脏对缺血损伤的易感性中的重要性。目的1：研究老年心脏缺血/再灌注时SIRT1的激活情况；目的2：探讨SIRT1在缺血再灌注应激过程中对心功能的调节作用；目的3：评价小分子AMPK或SIRT1激动剂改善老年心脏缺血/再灌注适应性反应的能力。通过这种方式，我们将促进我们对心脏SIRT1信号通路中与衰老相关的变化响应于缺血应激的机制的理解。此外，我们提出了一种新的治疗策略，可能上调心脏SIRT1信号，从而保护这部分人群免受缺血诱导的心脏损伤。

 DESCRIPTION (provided by applicant): Clinical studies report a higher incidence of ischemic heart disease and mortality after myocardial infarction, coronary angioplasty, or cardiac surgery in patients older than 60 years of age, which appear to be related to a decline in intrinsic myocardial resistance to injury. The mechanisms responsible for age-related ischemic intolerance are incompletely understood and the signaling pathways involved in regulating cellular responses to ischemia/reperfusion remain largely unknown. We recently reported that an aging-associated reduction in AMP-activated protein kinase (AMPK) signaling is an important contributing factor leading to increased sensitivity to ischemic stress via modulation of the glucose transporter (GLUT4) translocation. Intriguingly, Sirtuin 1 (SIRT1), a longevity protein, is emerging as a potential AMPK downstream target involved in heart disease. Therefore, it is hypothesized that the impaired AMPK-SIRT1 signaling cascade in the aged heart contributes to intolerance to ischemic insults in the elderly. We will test this hypothesis to investigate the importance of SIRT1 signaling in the susceptibility of the aged heart to ischemic insults. Aim 1: To characterize the SIRT1 activation in the aged heart during ischemia/reperfusion; Aim 2: To determine the role of SIRT1 in regulating cardiac function during ischemia-reperfusion stress; Aim 3: To evaluate the capability of a small-molecule AMPK or SIRT1 agonist to improve ischemia/reperfusion-induced adaptive response in the aged heart. In this manner, we will advance our understanding of the mechanisms behind aging-associated alterations in cardiac SIRT1 signaling pathways in response to ischemic stress. Furthermore, we propose a novel therapeutic strategy that might up-regulate cardiac SIRT1 signaling and thus protect against ischemia- induced cardiac injury in this segment of population.