Alterations in Heart Stress Signaling during Ischemia with Aging

描述（由申请人提供）：在衰老过程中发生的心脏变化导致心肌功能下降，使其更容易受到损伤。心肌损伤的常见原因是缺血性损伤。到目前为止，缺乏将缺血应激耐受性下降与特定应激信号通路的改变联系起来的实验证据。最近，我们发现amp激活的蛋白激酶（AMPK）信号通路在限制心肌缺血/再灌注引起的心肌坏死、凋亡和功能障碍中起重要作用，衰老相关的AMPK活性降低可能是骨骼肌衰老相关的线粒体功能降低和细胞内脂质代谢失调的重要因素。申请人假设衰老与心肌细胞对急性缺血性损伤激活宿主反应的能力下降有关，这有助于降低对缺血性损伤的耐受性。我们将通过使用年轻（4-6个月大）和老年（24-26个月大）Fisher 344大鼠和C57BL/6小鼠的心脏来验证这一假设：1)检查老年心脏在临床上重要的缺血/再灌注应激下是否表现出AMPK应激信号上游介质的激活受损，并研究这种信号改变的机制。ii)确定衰老对缺血心脏中应激诱导的AMPK信号通路多因子下游效应物的影响，阐明应激信号在衰老中缺血耐受性受损中的作用。该研究旨在探讨衰老过程中AMPK激活缺陷是否会导致下游信号传导减少以及心肌对缺血/再灌注损伤的易感性增加。AMPK缺陷（KD）转基因小鼠和AMPK的药理学刺激将被用来证明AMPK在维持缺血耐受中的重要作用。我们还概述了未来的实验，以研究调节行为（即热量摄入和运动）对老年心脏AMPK信号通路的影响，以阐明可能导致AMPK刺激的干预措施在老年心血管疾病管理中的潜在作用。更好地了解随着年龄增长导致缺血应激改变心脏AMPK激活的机制，对于充分了解老年人对缺血性损伤易感性增加的基础非常重要，并可能导致旨在限制心脏损伤的治疗策略。

DESCRIPTION (provided by applicant): Alterations in the heart that occur during the aging process result in decreased myocardial function and render it more susceptible to damage. A common cause of damage to the myocardium is ischemic injury. Until now, experimental evidence linking a decline in ischemic stress tolerance to alterations in specific stress signaling pathways has been lacking. Recently, we have found that the AMP-activated protein kinase (AMPK) signaling pathway plays an important role in limiting cardiac necrosis, apoptosis and dysfunction induced by ischemia/reperfusion, and aging-associated reduction in AMPK activity that may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with aging in skeletal muscles. The applicant hypothesizes that aging is associated with a decline in the ability of cardiac cells to activate this host response to acute ischemic injury, which contributes to a reduced tolerance to ischemic insults. We will test this hypothesis by addressing the following specific aims using hearts from young (4-6 months of age) and old (24-26 months of age) Fisher 344 rats and C57BL/6 mice: i) to examine whether aged heart displays impaired activation of upstream mediators of AMPK stress signaling by clinically important ischemia/reperfusion stress and to investigate the mechanisms responsible for this alteration in signaling. ii) to determine the effects of aging on the multifactorial downstream effectors of stress-induced AMPK signaling pathways in the ischemic heart, and to elucidate the role of stress signaling in impaired ischemic tolerance in aging. This aim will address whether defective AMPK activation with aging leads to reduced downstream signaling and increased susceptibility of the myocardium to ischemia/reperfusion injury. AMPK deficient (KD) transgenic mice and pharmacologic stimulation of AMPK will be used to demonstrate the important role of AMPK in maintaining ischemic tolerance. We also outline future experiments to examine the effect of modulating behaviors, namely caloric intake and exercise, on the AMPK signaling pathway in the aged heart, to elucidate the potential role of interventions that might lead to AMPK stimulation in managing cardiovascular disease in the elderly. Better understanding of the mechanisms leading to altered cardiac AMPK activation in response to ischemic stress with aging is important to fully understand the basis for increased susceptibility of the elderly to ischemic injury and could lead to therapeutic strategies aimed at limiting cardiac damage.