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，短暂的缺血时期，即缺血性预处理（IPC），从随后的缺血/再灌注损伤中为心肌提供了强大的自我保护。但是，最近的证据表明，IPC在人类和高龄的动物中受到严重损害，该组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，尚不提供为衰老心脏提供有效的心肌保护的新的药理学干预措施。对于这个试点项目，我们的具体目标是研究缺血性预处理中与年龄相关的缺陷的细胞机制； b。要探索短暂暴露于挥发性麻醉剂二氟烷（即麻醉预处理（APC））是否为缺血 - 重新灌注损伤的老年心脏提供心肌保护。来自年轻（6个月大）和衰老（28个月大）的Fisher 344只大鼠的孤立的灌注心脏将受到IPC或APC的约束，随后是缺血和再灌注。胞质和线粒体Ca2+（通过Indo-1）和线粒体代谢（NADH荧光）在左心室中的代谢（NADH荧光）将通过光纤探针实时监测。使用蛋白质印迹，将通过梗死大小，肌膜网状，线粒体，肌膜，肌膜和细胞骨架来评估心肌保护。线粒体KATP通道和小热休克蛋白在心肌保护中的特定作用将被探索。这些参数将对IPC中与年龄相关的缺陷提供系统的看法，并显示APC是否可以有效保护衰老的心脏。作为该实验室的新研究领域，该项目的长期目标是调查可能保护老年心肌免受缺血/再灌注损伤的新干预措施。