Mitochondria and surgical myopreservation in aging

衰老过程中的线粒体和手术肌肉保存

• 批准号: 6795823
• 负责人: ARSHAD JAHANGIR
• 金额: $ 28.9万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6795823
• 关键词: adenosine triphosphate; age difference; animal old age; bioenergetics; calcium flux; cardiac myocytes; cardiovascular agents; cell senescence; cytoprotection; diazoxide; guanidines; heart metabolism; laboratory rat; mitochondria; myocardial ischemia /hypoxia; oxidative stress; physiologic stressor; potassium channel; reperfusion; stress; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): During open-heart surgery, the myocardium is subjected to varying periods of global ischemia. The resulting ischemia - reperfusion injury contributes to postoperative cardiac dysfunction, especially in the elderly. Indeed, the aged myocardium is highly vulnerable to metabolic injury and demonstrates a deficient capacity to restore cellular energetics and ionic balance on reperfusion. Although the subcellular mechanisms underlying the reduced tolerance of the senescent heart to metabolic stress are not fully understood, mitochondrial Ca2+ overload and associated energetic failure have been proposed to play a significant role in myocardial dysfunction in the elderly. However, measures to prevent mitochondrial dysfunction in the senescent myocardium are lacking. Our preliminary results indicate that modulation of the activity of a metabolic sensor, recognized as the mitochondrial ATP-sensitive K+ (mitoKATP) channel, effectively prevents mitochondrial Ca2+ overload, and preserves mitochondrial functional and structural integrity under metabolic stress. Therefore, we here hypothesize that activation of mitoKATP channels by pharmacological and/or genetic means could provide a strategy for enhanced tolerance of the senescent myocardium to ischemic stress. The specific aims of this proposal are: I) to define the protective potential of mitoKA1-P channel openers in the preservation of the senescent myocardium, ii) to determine the mechanisms underlying mitochondria-dependent protection of the senescent mitochondria, and iii) to engineer stress-tolerant cardiac cells through mitochondrial over-expression of KATP channel genes. The proposed specific aims will be tested in adult and senescent isolated mitochondria, and wild type and genetically engineered cardiac cells and then translated to the whole organ level. The significance of this proposal is in establishing a novel principle of myopreservation of the senescent heart by targeting protection of mitochondrial homeostasis and associated energetic pathways. This is especially relevant for cardiac surgery in the elderly, with the ultimate goal of limiting post-bypass pump failure.

描述（由申请人提供）：在心脏直视手术期间，心肌会经历不同时期的整体缺血。 由此产生的缺血-再灌注损伤会导致术后心功能障碍，尤其是老年人。 事实上，老化的心肌非常容易受到代谢损伤，并且在再灌注时恢复细胞能量和离子平衡的能力不足。 尽管衰老心脏对代谢应激耐受性降低的亚细胞机制尚不完全清楚，但线粒体 Ca2+ 超载和相关的能量衰竭已被认为在老年人心肌功能障碍中发挥着重要作用。 然而，缺乏预防衰老心肌线粒体功能障碍的措施。 我们的初步结果表明，调节代谢传感器（被认为是线粒体 ATP 敏感 K+ (mitoKATP) 通道）的活性，可以有效防止线粒体 Ca2+ 过载，并在代谢应激下保持线粒体功能和结构完整性。 因此，我们在此假设通过药理学和/或遗传手段激活mitoKATP通道可以提供增强衰老心肌对缺血应激的耐受性的策略。 该提案的具体目标是：I) 确定 mitoKA1-P 通道开放剂在保存衰老心肌中的保护潜力，ii) 确定衰老线粒体的线粒体依赖性保护的潜在机制，以及 iii) 设计通过线粒体 KATP 通道基因的过度表达来耐受应激的心肌细胞。 所提出的具体目标将在成人和衰老的分离线粒体、野生型和基因工程心脏细胞中进行测试，然后转化为整个器官水平。 该提案的意义在于通过针对线粒体稳态和相关能量通路的保护，建立了衰老心脏心肌保护的新原理。 这对于老年人的心脏手术尤其重要，其最终目标是限制旁路术后泵衰竭。