Myocardial Protection in the Aging Heart

已经证实，短暂的缺血，即缺血预适应(IPC)，对随后的缺血/再灌注损伤具有强大的自我保护作用。然而，最近的证据表明，在人类和高龄动物中，IPC受到严重损害，这两组人最有可能患有急性心绞痛/心肌梗死。这种与年龄相关的缺陷的机制还不是很清楚。此外，模拟IPC的新的药物干预措施对老化的心脏提供有效的心肌保护尚不存在。在这个试点项目中，我们的具体目标是：a，研究缺血预适应中与年龄相关的缺陷的细胞机制；b，探讨短暂暴露于挥发性麻醉剂七氟醚，即麻醉预适应(APC)，是否能为老年心脏提供心肌保护，使其免受缺血-再灌注损伤。将青年(6月龄)和老年(28月龄)Fisher 344大鼠的离体灌流心脏分别进行IPC或APC，然后进行缺血再灌流。将使用光纤探头实时监测左心室内的胞浆和线粒体钙离子(用INDO-1检测)和线粒体代谢(NADH荧光)。心肌保护将通过心肌梗死面积、肌浆网、线粒体、肌丝、肌膜和细胞骨架的完整性来评估。将探讨线粒体KATP通道和小分子热休克蛋白在心肌保护中的具体作用。这些参数将提供IPC中与年龄相关的缺陷的系统视图，并显示APC是否能有效地保护老化的心脏。作为本实验室的一个新的研究领域，本项目的长期目标是探索新的干预措施，以保护老年心肌免受缺血/再灌注损伤。

It is well established that brief periods of ischemia, i.e. ischemic preconditioning (IPC) offers powerful self-protection of the myocardium from subsequent ischemia/reperfusion injury. However, recent evidence indicate that IPC is severely compromised in humans and animals with advanced age, which group is most likely to suffer from acute angina/myocardial infarct. The mechanisms of this age-related defect is not well understood. Further more, new pharmacological interventions mimicking IPC which offer effective myocardial protection for the aging heart are not yet available. For this pilot project, our specific aims are a, to investigate the cellular mechanisms of age-related defects in ischemic preconditioning; b. to explore whether brief exposure to volatile anesthetic sevoflurane, i.e. anesthetic preconditioning (APC), offers myocardial protection for the aged heart from ischemia-reperfusion injury. Isolated perfused hearts from young (6 months old) and senescent (28 months old) Fisher 344 rats will be subjected to IPC or APC followed by ischemia and reperfusion. Cytosolic and mitochondrial Ca2+ (detected by Indo-1) and mitochondria metabolism (NADH fluorescence) in left ventricles will be monitored real time with fiber optic probes. Myocardial protection will be evaluated by infarct size, integrity of sarcoplasmic reticulum, mitochondria, myofilaments, sarcolemma, and cytoskeleton using western blots. The specific role of mitochondrial KATP channels and small heat shock proteins in myocardial protection will be explored. These parameters will provide a systematic view of the age-related defect in IPC and show whether APC can effectively protect the aging heart. The long term objectives of this project, as a new research area for this laboratory, are to investigate new interventions which may protect the aged myocardium from ischemia/reperfusion injury.