Role of Sestrin2 in Prevention of Age-related Cardiomyopathy

项目总结/摘要 总的目标是阐明心脏中促进心肌细胞凋亡的分子和生理机制。 对老年人心肌缺血和缺血/再灌注（I/R）损伤的心脏保护作用。随着衰老， 心肌耐受缺血性应激的能力受到损害。因此， 70岁以上接受当前心肌介入治疗的患者的发病率和死亡率 梗塞然而，在I/R的适应性反应中， 仍然不完全理解。因此，了解这些机制在 衰老的心脏是改善针对此类心血管疾病的治疗策略的基础。 病理学我们的团队和其他人提供了大量的证据表明，AMP的激活- 活化蛋白激酶（AMPK）信号通路对心脏非常有利。而且我们 最近证明，在心肌缺血期间，AMPK激活在老年人中显著受损， 这与心肌梗死和心功能不全的增加直接相关。 然而，除了内源性机制外，AMPK在心肌缺血期间如何被激活， 解释在年轻和老年心脏之间观察到的AMPK激活受损的差异仍然存在 很难捉摸最近，一组新的缺乏激酶活性的蛋白质，称为sestrins，特别是 已证明Sestrin 2在体外和体内增加AMPK的活化。Sestrin 2也限制了 细胞死亡对缺氧损伤，限制氧化应激，并增加自噬通量，所有这些都是 在老年性心功能不全中很重要。因此，我们假设Sestrin 2可能是一个积分， 在心肌I/R期间发生的应激反应的一部分，以及它与AMPK信号传导的合作， 通路随着心脏衰老而改变。这个假设将以两个目标进行检验。首先，我们的目标是 将sestrin 2定义为I/R损伤期间适应性反应的关键组分。第二，我们的目标是 表征Sestrin 2如何参与老年心脏I/R期间受损的AMPK信号通路。 拟议的研究采取跨学科的方法，包括生理相关的体内， 衰老和I/R损伤的离体模型。通过这种方式，拟议的研究将突出新的治疗方法， 目标，并进一步了解特定的应激激活的心脏保护途径是如何 因衰老而受损公共卫生相关性：缺血性心脏病，大约影响 每年有100万美国人死于心肌缺血，最常见的原因是缺血性损伤导致心肌损伤。 这项资助旨在了解受损的心脏保护信号传导导致更高的 老年人群缺血性心脏病的发病率，并有可能发现新的治疗方法 限制老年人心肌功能障碍的策略。

Project Summary/Abstract The overall goal is to elucidate the molecular and physiological mechanisms in the heart that promote cardioprotection against myocardial ischemia and ischemia/reperfusion (I/R) injury in the elderly. With aging, the ability of the myocardium to tolerate ischemic stress becomes compromised. Consequently, there is more morbidity and mortality in patients that are over 70 years of age receiving current interventions for myocardial infarction. Yet the mechanisms responsible for this age-related impairment in the adaptive response to I/R remains incompletely understood. Therefore, understanding the alteration of these mechanisms within the aging heart is fundamental for improving therapeutic strategies targeted against such cardiovascular pathologies. Our group and others have provided extensive evidence suggesting that activation of the AMP- activated protein kinase (AMPK) signaling pathway is highly advantageous to the heart. Moreover, we have recently demonstrated that during myocardial ischemia, AMPK activation is significantly impaired in the aged heart and that this is directly associated with increased myocardial infarction and cardiac dysfunction. However, how AMPK is activated during myocardial ischemia in addition to the endogenous mechanisms explaining the differences observed in impaired AMPK activation between young and aged hearts remains largely elusive. Recently, a novel group of proteins that lack kinase activity, known as the sestrins, particularly Sestrin2, have been demonstrated to increase the activation of AMPK in vitro and in vivo. Sestrin2 also limits cell death against hypoxic insults, limits oxidative stress, and increases the autophagic flux, all of which are important in age-related cardiac dysfunction. Accordingly, we hypothesize that Sestrin2 may be an integral part of the stress response that occurs during myocardial I/R and that its cooperation with the AMPK signaling pathway is altered with cardiac senescence. This hypothesis will be tested with two aims. First, we aim to define sestrin2 as a critical component of the adaptive response during I/R injury. Second, we aim to characterize how Sestrin2 is involved in the impaired AMPK signaling pathway during I/R in the aged heart. The proposed research takes an interdisciplinary approach encompassing physiologically relevant in vivo and ex vivo models of aging and I/R injury. In this manner, the proposed research will highlight new therapeutic targets and further our understanding about how specific stress-activated cardioprotective pathways are impaired with aging. PUBLIC HEALTH RELEVANCE: Ischemic heart disease, which affects approximately one million Americans each year, is most often caused by ischemic insults leading to myocardial damage. This grant seeks to understand the ways in which impaired cardioprotective signaling leads to a higher incidence of ischemic heart disease in the aged population, and has the potential to discover new therapeutic strategies to limit myocardial dysfunction in the elderly.