AMPK-SIRT1 Signaling in the Adaptive Metabolic Response

 描述（由申请人提供）：临床研究报告，在60岁以上的患者中，心肌梗死、冠状动脉血管成形术或心脏手术后缺血性心脏病的发病率和死亡率较高，这似乎与心肌对损伤的内在抵抗力下降有关。年龄相关的缺血性不耐受的机制还不完全清楚，参与调节细胞对缺血/再灌注反应的信号转导途径在很大程度上仍然未知。我们最近报道，年龄相关的AMP活化蛋白激酶（AMPK）信号转导的减少是一个重要的促成因素，导致增加敏感性缺血应激通过调节葡萄糖转运蛋白（GLUT 4）易位。有趣的是，Sirtuin 1（SIRT 1），一种长寿蛋白， 成为心脏病中潜在的AMPK下游靶点。因此，假设老年心脏中受损的AMPK-SIRT 1信号级联有助于老年人对缺血性损伤的不耐受。我们将检验这一假设，以研究SIRT 1信号在老年心脏对缺血性损伤的易感性中的重要性。目标1：目的2：研究老年心脏缺血再灌注时SIRT 1的活化;目的3：研究小分子AMPK或SIRT 1激动剂对老年心脏缺血再灌注诱导的适应性反应的影响。通过这种方式，我们将进一步了解心脏SIRT 1信号通路响应缺血应激的衰老相关改变背后的机制。此外，我们提出了一种新的治疗策略，可能上调心脏SIRT 1信号转导，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.