Myocardial Protection in the Aging Heart

已经证实，短暂的缺血，即缺血预处理（IPC）提供了心肌对随后的缺血/再灌注损伤的强有力的自我保护。然而，最近的证据表明，IPC在人类和老年动物中严重受损，这组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清楚。此外，还没有新的药物干预模仿IPC，提供有效的心肌保护老化的心脏。对于这个试点项目，我们的具体目标是a，研究缺血预处理中年龄相关缺陷的细胞机制; B。探讨吸入麻醉药七氟醚短暂暴露，即麻醉预处理（APC），是否对老年心脏缺血再灌注损伤具有心肌保护作用。将来自年轻（6个月大）和衰老（28个月大）Fisher 344大鼠的分离的灌注心脏进行IPC或APC，随后进行缺血和再灌注。将使用光纤探针真实的时间监测左心室中的细胞溶质和线粒体Ca 2+（通过Indo-1检测）和线粒体代谢（NADH荧光）。采用蛋白质印迹法，通过梗死面积、肌浆网、线粒体、肌丝、肌膜和细胞骨架的完整性评价心肌保护。线粒体KATP通道和小的热休克蛋白在心肌保护中的具体作用将被探讨。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是否可以有效地保护老化的心脏。本课题作为本实验室的一个新的研究领域，其长期目标是研究新的干预措施，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.