Enhancing Cardiac Protection

描述(由申请人提供)： 心肌缺血/再灌注损伤仍然是世界范围内发病率和死亡率的主要原因。20世纪80年代S发现的缺血预适应揭示了存在一种有效的内源性保护机制来提高心脏的缺血耐受性，这种机制可以通过在长时间的缺血/再灌流事件之前的短暂的缺血和再灌流而产生。缺血后处理是在缺血组织再灌流之前诱发的，为心脏保护提供了一个临床相关的靶点。许多内源性配体和药物，包括挥发性麻醉药，在心脏产生预适应和后适应，提供对心肌缺血/再灌注损伤的心脏保护。尽管在过去的30年里，在心脏保护机制方面取得了重大的进展，但在临床环境中充分利用预适应和后适应的潜力仍然没有实现。临床环境中的心脏保护策略受到多种因素的限制，包括年龄和与衰老相关的疾病。我们以前已经证明，参与心脏保护的信号分子需要在小窝内发挥作用，并与小窝蛋白相互作用，以产生有效的心脏保护。我们建议检验这一新的假说，即小窝蛋白的丢失和小窝微区内精确的心脏保护信号的中断会导致挥发性麻醉剂诱导的心脏保护信号在老年动物中明显受损，而小窝蛋白的重新表达可以恢复因衰老而受损的挥发性麻醉剂诱导的心脏保护信号。该赠款的目的将1：确定涉及挥发性麻醉剂和小凹蛋白在年轻和老年心肌细胞的肌膜相互作用的机制；2：确定挥发性麻醉剂诱导的心肌保护信号分子、小窝蛋白和线粒体在年轻和老年心肌细胞中相互作用的机制；3：确定过表达Cav-3是否恢复了挥发性麻醉剂诱导的老年小鼠和人类心脏的心脏保护。我们将利用最先进的分子生物学技术、电子顺磁共振技术、成像技术和生理学技术，在心肌细胞、人类心肌和临床相关的I/R损伤模型中，专注于机制并产生重要的临床前数据，以支持将小窝蛋白作为新的治疗方法用于面临心肌缺血/再灌注损伤风险的老年退伍军人患者。

DESCRIPTION (provided by applicant): Myocardial ischemia/reperfusion injury remains a major cause of morbidity and mortality worldwide. The discovery of ischemic preconditioning in the 1980's revealed the presence of a potent endogenous protective mechanism to increase ischemic tolerance in the heart that could be produced by brief periods of ischemia and reperfusion preceding a prolonged ischemia/reperfusion event. Ischemic postconditioning, evoked prior to reperfusion of ischemic tissue, has provided a clinically relevant target for cardiac protection. Numerous endogenous ligands and pharmaceuticals, includeing volatile anesthetics, produce pre and post conditioning in the heart, providing cardiac protection from myocardial ischemia/reperfusion injury. Despite significant insights gained over the last 30 years into mechanisms of cardiac protection, the full potential of harnessing pre and post conditioning in the clinical setting remains unfulfilled. Cardiac protection strategies in the clinical setting are limited by several factors including age and diseases related to aging. We have shown previously that the signaling molecules involved in cardioprotection need to function within caveolae and interact with caveolins to produce effective cardioprotection. We propose to test the novel hypothesis that loss of caveolin and disruption of precise cardioprotective signaling within caveolar microdomains results in the impaired volatile anesthetic-induced cardiac protection evident in aged animals and that re- expression of caveolin can restore volatile anesthetic-induced cardiac protective signaling that has been impaired by aging. The aims of the grant will 1: Determine mechanisms involved the interaction of volatile anesthetics and caveolins at the sarcolemmal membrane in young and aged cardiac myocytes, 2: Determine the mechanisms involved in the interaction of volatile anesthetic-induced cardioprotective signaling molecules, caveolins and mitochondria in young and aged cardiac myocytes, and 3: Determine if overexpression of Cav-3 restores volatile anesthetic-induced cardiac protection in aged mice and human hearts. We will use state of the art molecular biology techniques, electron paramagnetic resonance technology, imaging technology, and physiological techniques in cardiac myocytes, human myocardium and clinically relevant models of I/R injury to focus on mechanism and produce important preclinical data to support the use of caveolins as novel therapeutics for aged veteran patients at risk of myocardial ischemia/reperfusion injury.