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，使其更容易受到损害。心肌损伤的常见原因是缺血性损伤。到目前为止，缺乏将缺血性应激耐受性下降与特定应激信号通路改变联系起来的实验证据。近年来，我们发现AMPK信号通路在限制缺血/再灌注引起的心肌坏死、凋亡和功能障碍中起重要作用，并且AMPK活性的衰老相关降低可能是骨骼肌中与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，衰老与心脏细胞激活这种对急性缺血性损伤的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人的心脏来解决以下具体目标来验证这一假设（4-6个月）和老年人（24-26月龄）Fisher 344大鼠和C57 BL/6小鼠：i）检查老年心脏是否表现出由临床上重要的缺血引起的AMPK应激信号传导的上游介质的活化受损，再灌注应激，并调查负责这种信号转导改变的机制。ii）确定衰老对缺血心脏中应激诱导的AMPK信号通路的多因素下游效应物的影响，并阐明应激信号在衰老中缺血耐受受损中的作用。这一目标将解决是否有缺陷的AMPK激活与老化导致下游信号减少和增加心肌缺血/再灌注损伤的易感性。AMPK缺陷（KD）转基因小鼠和AMPK的药理学刺激将用于证明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，以检查调节行为的影响，即热量摄入和运动，在老年心脏的AMPK信号通路，以阐明可能导致AMPK刺激在管理老年人心血管疾病的干预措施的潜在作用。更好地了解导致心脏AMPK激活改变的机制，以应对随着年龄的增长而出现的缺血性应激，对于充分了解老年人对缺血性损伤的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.