Role of Sestrin2 in Prevention of Age-related Cardiomyopathy

项目摘要/摘要 总体目标是阐明促进心脏功能的分子和生理机制。 老年人对心肌缺血和缺血/再灌注损伤的心脏保护作用。随着年龄的增长， 心肌对缺血应激的耐受能力受到损害。因此，还有更多 接受当前心肌梗死介入治疗的70岁以上患者的发病率和死亡率 脑梗塞。然而，在对I/R的适应性反应中，这种与年龄相关的损害的机制 仍然没有完全被理解。因此，理解这些机制在 心脏老化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已经提供了广泛的证据表明，AMP- 活化蛋白激酶(AMPK)信号通路对心脏非常有利。此外，我们有 新近发现，在心肌缺血时，AMPK的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有直接关系。 然而，除了内源性机制外，AMPK在心肌缺血时是如何被激活的 解释年轻心脏和老年心脏AMPK激活受损的差异 在很大程度上是难以捉摸的。最近，一组新的缺乏激酶活性的蛋白质，被称为Sestrins，特别是 Sestrin2，已被证明在体外和体内都能增加AMPK的活性。Sestrin2也限制了 细胞死亡抵抗低氧侮辱，限制氧化应激，增加自噬通量，所有这些都是 在与年龄相关的心功能不全中很重要。因此，我们假设Sestrin2可能是一个积分 心肌I/R过程中应激反应的一部分及其与AMPK信号的协同作用 随着心脏的衰老，信号转导途径发生改变。这一假设将通过两个目标进行检验。首先，我们的目标是 将sestrin2定义为I/R损伤期间适应性反应的关键组成部分。第二，我们的目标是 描述Sestrin2如何参与老年心脏I/R期间受损的AMPK信号通路。 拟议的研究采取了跨学科的方法，包括体内生理相关和 衰老和I/R损伤的体外模型。通过这种方式，拟议的研究将突出新的治疗方法 靶点和进一步了解特定的应激激活的心脏保护通路是如何 因年龄增长而受损的。公共卫生相关性：缺血性心脏病，它影响大约 每年有100万美国人，最常见的是由导致心肌损伤的缺血性侮辱引起的。 这项拨款旨在了解心脏保护信号受损导致较高的 老年人群中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.