Mechanisms of Intrinsic Cardioprotection in Marmota momax

描述（由申请人提供）：哺乳动物冬眠是一种独特的冬季生存策略，以应对有限的食物供应和恶劣的气候。在体温较低的非冬眠动物中观察到，冬眠动物的心脏对室性心律失常/纤颤表现出显著的耐受性和抵抗力。冬眠哺乳动物可能是一种具有独特天然心脏保护作用的模型，用于研究心肌缺血性疾病的新机制。我们观察到冬眠的哺乳动物如旱獭（旱獭）从夏季到冬季表现出表型的变化。与旱獭相比，旱獭在冬季对缺血/再灌注（I/R）损伤表现出强大的心肌保护作用，与缺血预处理所阐明的结果相似。事实上，冬眠的动物是通过唤醒它们内在的心脏保护机制来为冬天做准备的。我们的初步结果还表明，cAMP反应元件结合蛋白（CREB）是一种调节细胞存活和凋亡重要基因表达的核转录因子，在冬季和冬眠期间在土旱獭心脏中被显著激活，甚至更高。我们假设CREB的激活是一种潜在的新分子，在冬季土拨鼠的心脏中介导这种心脏保护。本提案的目标是：(1)研究CREB在介导心脏保护中的重要性，并确定与CREB相关的其他关键信号分子，这些信号分子可以保护心脏免受心肌缺血后的凋亡和坏死；(2)探讨传统IPC介导机制是否也参与到旱獭冬季心脏保护中。长期目标是揭示冬眠哺乳动物自然抵抗心脏应激的细胞和分子机制，并揭示心脏保护的主“开关”。这对医疗保健的意义是明确的：了解冬眠动物的心脏适应机制可能为保护非冬眠动物（尤其是人类）的心肌免受低温应激和心肌缺血引起的心功能障碍提供新的策略。项目描述：对医疗保健的意义是明确的：了解冬眠动物的心脏适应机制可能为保护非冬眠动物（尤其是人类）的心肌免受低温应激和心肌缺血引起的心功能障碍提供新的策略。

DESCRIPTION (provided by applicant): Mammalian hibernation is a unique strategy for winter survival in response to limited food supply and harsh climate. The hearts of hibernators exhibit remarkable tolerance and resistance to the ventricular arrhythmias/fibrillation that is observed in non-hibernators at lower body temperature. Hibernating mammals may be a model with unique natural cardioprotection to investigate novel mechanisms involved in myocardial ischemic disease. We observed that hibernating mammals such as woodchucks (Marmota monax) demonstrate a changed phenotype from summer to winter. They exhibit powerful myocardial protection in the winter against ischemia/reperfusion (I/R) injury compared to woodchucks in summer, similar to that elucidated by ischemic preconditioning. In fact, hibernating animals are "prepared" for winter by evoking their intrinsic cardioprotective mechanisms. Our preliminary results also demonstrate that the cAMP response element binding protein (CREB), a nuclear transcription factor, which regulates the expression of genes important for cell survival and apoptosis, is significantly activated in the woodchuck hearts in winter and even higher during hibernation. We hypothesize that the activation of CREB is a potentially novel molecule mediating this cardioprotection in the hearts of woodchucks in winter. The goal of this proposal is to (1) investigate the importance of CREB in mediating cardioprotection and to identify other key signaling molecules linked to CREB which protect the heart against apoptosis and necrosis following a myocardial ischemic instance; (2) examine whether mechanisms mediating traditional IPC are also involved in the cardioprotection observed in the woodchuck heart in the winter. The long term goal is to reveal the cellular and molecular mechanisms involved in natural resistance to cardiac stresses in hibernating mammals and to uncover the master "switch" for cardioprotection. The implications for health care are clear: understanding the cardiac adaptive mechanisms in hibernators may suggest new strategies to protect myocardium of non-hibernating animals, especially humans, from cardiac dysfunction induced by hypothermic stresses and myocardial ischemia.PROJECT NARRATIVE: The implications for health care are clear: understanding the cardiac adaptive mechanisms in hibernators may suggest new strategies to protect myocardium of non-hibernating animals, especially humans, from cardiac dysfunction induced by hypothermic stresses and myocardial ischemia.