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: 6649832
• 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/6649832
• 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; 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）：在开放性手术期间，心肌受到不同时期的全球性缺血时期。 由此产生的缺血 - 再灌注损伤导致术后心脏功能障碍，尤其是在老年人中。 实际上，老化的心肌非常容易受到代谢损伤的影响，并且表现出恢复细胞能量和再灌注时离子平衡的能力不足。 尽管尚未完全了解衰老心脏对代谢应激的耐受性降低的基础机制，但已经提出了线粒体Ca2+过载和相关的能量失效，以在老年人的心肌功能障碍中发挥重要作用。 但是，缺乏防止线粒体功能障碍的措施。 我们的初步结果表明，代谢传感器的活性的调节，被公认为是线粒体ATP敏感的K+（MitoKATP）通道，有效地防止了线粒体CA2+过载，并保留了线粒体功能和结构性整合在代谢压力下。 因此，我们在这里假设通过药理学和/或遗传手段激活MitokATP通道可以提供一种策略，以增强对缺血性压力的衰老心肌的耐受性。 该提案的具体目的是：i）定义Mitoka1-P通道开瓶器在保存衰老心肌方面的保护潜力，ii）确定线粒体依赖于衰老线粒体的保护的机制，以及III的III），以通过Mitochrial Extectression knectrycression knectrycression knectrycression kate katipression katipression katipression katipression katipression katipsection kat katip noce n katip cannel cante noce canterrip cannel nightiage。 提出的特定目标将在成人和衰老的分离线粒体以及野生型和基因工程性心脏细胞中进行测试，然后转化为整个器官水平。 该提议的意义在于通过靶向线粒体稳态和相关的能量途径来建立衰老心脏肌屈服的新原则。 这与老年人的心脏手术尤其重要，其最终目的是限制Bypass Pump衰竭。