Alterations in Heart Stress Signaling during Ischemia with Aging

描述(申请人提供)：在衰老过程中发生的心脏变化会导致心肌功能下降，使其更容易受到损害。心肌损伤的一个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)信号通路在限制缺血/再灌注引起的心肌坏死、细胞凋亡和功能障碍以及增龄性AMPK活性降低方面发挥着重要作用，这可能是骨骼肌线粒体功能降低和细胞内脂质代谢异常的重要因素。申请人假设，衰老与心肌细胞激活宿主对急性缺血损伤的反应的能力下降有关，这导致对缺血损伤的耐受性降低。我们将通过使用年轻(4-6月龄)和老年(24-26月龄)Fisher 344大鼠和C57BL/6小鼠的心脏来验证这一假说：i)检查老年心脏是否表现出AMPK应激信号上游介质的激活受损，并探讨这种信号变化的机制。Ii)研究衰老对心肌缺血应激诱导的AMPK信号通路多因子下游效应的影响，阐明应激信号在衰老心肌缺血耐受受损中的作用。这一目标将解决AMPK激活缺陷是否随年龄增长导致下游信号减少和心肌对缺血/再灌注损伤敏感性增加的问题。AMPK基因缺陷(KD)转基因小鼠和AMPK的药理刺激将被用来证明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，以检验调节行为，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刺激的干预在老年人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心脏AMPK活性变化的机制，对于充分了解老年人对缺血性损伤易感性增加的基础是重要的，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.