Myocardial Protection in the Aging Heart

衰老心脏的心肌保护

• 批准号: 6614912
• 负责人: DAVID F STOWE
• 金额: $ 7.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6614912
• 关键词: adenosine triphosphate; age difference; aging; anesthetics; angina pectoris; animal old age; calcium flux; chemoprevention; cytoplasm; cytoprotection; fiber optics; heart pharmacology; heat shock proteins; isoflurane; isolation perfusion; laboratory rat; mature animal; mitochondria; myocardial infarct sizing; myocardial infarction; myocardial ischemia /hypoxia; myocardium; potassium channel; reperfusion; technology /technique development; western blottings

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.

众所周知，短暂的缺血，即缺血预适应（IPC）可以为心肌提供强大的自我保护，使其免受随后的缺血/再灌注损伤。然而，最近的证据表明，IPC 在高龄人类和动物中受到严重损害，这些群体最有可能患有急性心绞痛/心肌梗塞。这种与年龄相关的缺陷的机制尚不清楚。此外，尚无模仿 IPC 的新药物干预措施，为衰老的心脏提供有效的心肌保护。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，即麻醉预处理（APC）是否可以为老年心脏提供心肌保护，使其免受缺血再灌注损伤。来自年轻（6 个月大）和衰老（28 个月大）Fisher 344 大鼠的离体灌注心脏将接受 IPC 或 APC，然后进行缺血和再灌注。将使用光纤探针实时监测左心室中的细胞质和线粒体 Ca2+（通过 Indo-1 检测）以及线粒体代谢（NADH 荧光）。将使用蛋白质印迹通过梗死面积、肌浆网、线粒体、肌丝、肌膜和细胞骨架的完整性来评估心肌保护。将探讨线粒体KATP通道和小热休克蛋白在心肌保护中的具体作用。这些参数将为 IPC 中与年龄相关的缺陷提供系统的视图，并显示 APC 是否可以有效保护衰老的心脏。作为该实验室的一个新研究领域，该项目的长期目标是研究可以保护老化心肌免受缺血/再灌注损伤的新干预措施。