Human Senescence and Cardioprotection

人类衰老与心脏保护

• 批准号: 7461360
• 负责人: ARSHAD JAHANGIR
• 金额: $ 37.78万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2008-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7461360
• 关键词: Address; Adult; Affect; Age; Aging; Animal Model; Biology; Bypass; Calcium; Cardiac; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular system; Cell Membrane Permeability; Cell physiology; Cellular Stress; Complex; Condition; Defect; Defense Mechanisms; Development; Disease Progression; Disruption; Distress; Down-Regulation; Elderly; Elements; Failure; Gene Expression; Genes; Genomics; Heart; Heart Atrium; Homeostasis; Human; Human Rights; Individual; Injury; Inner mitochondrial membrane; Ischemic Preconditioning; Link; Mediating; Membrane Potentials; Metabolic; Mitochondria; Molecular; Molecular Genetics; Muscle Cells; Myocardial; Myocardial dysfunction; Myocardium; Numbers; Operative Surgical Procedures; Oxidants; Pathology; Pathway interactions; Patients; Phenotype; Pilot Projects; Post-Translational Protein Processing; Potassium; Predisposition; Prevalence; Production; Proteins; Proteomics; Public Health; Regulation; Rodent; Signal Pathway; Signal Transduction; Signaling Protein; Stress; Tissues; age effect; age related; aged; attenuation; auricular appendage; base; cardiogenesis; clinically significant; density; disability; interest; mitochondrial membrane; mitochondrial permeability transition pore; older patient; prevent; protective effect; protein protein interaction; response; senescence; sensor; therapeutic target

DESCRIPTION (provided by applicant): Aging increases cardiovascular disability, yet the molecular basis for increased stress susceptibility of the senescent human myocardium remains unknown. Particularly little is known about the atria, despite the exponential increase in the prevalence of atrial electrical and structural abnormalities with advancing age. Our preliminary studies in aging rodents demonstrate an age-associated loss of endogenous cardioprotection associated with reduction in mitochondrial energetic reserves and disruption of myocardial capacity for transduction of stress signals into protective responses. Deficient in defense mechanisms, the aging rodent heart can however be protected by modulation of mitochondrial membrane potential and activation of the ATP- sensitive potassium (KATP) channel. Whether aging-associated loss of endogenous cardioprotective responses also occurs in aged human atria is not clear. In pilot studies, using atrial tissue from adult and aged patients, a distinct transcriptional downregulation of genes regulating mitochondrial energetics and cardioprotective pathways, including the human KATP channel metabolic decoder subunit, was demonstrated in aging heart. We hypothesize that the increased vulnerability of the senescent human atria to injury results from an aging- associated attenuation in energetic homeostasis that sensitizes the myocardium to energetic failure, calcium overload and increased oxidants during stress. We propose to define age-related i) changes in energetic homeostasis in human atria and its functional consequences on tolerance to stress; ii) mechanisms that underlie age-related changes in energetics with focus on pathways that link energy production with energy sensing and utilization pathways; and iii) rescue senescent human atrial myocytes and mitochondria from stress-induced injury by modulation of stress responsive homeostatic pathways. These aims will be achieved using human right atrial appendage obtained during surgery from adult (35-55 years) and elderly (65-85 years) patients. The novelty of the proposed studies is to obtain functional, molecular, genetic and proteomic information from the same human atrial tissue to characterize age-related changes in cardiac energetics, metabolic and cardioprotective signaling, protein-protein interactions and cellular physiology under baseline and stress conditions. Information on the sensitivity of human aged and adult atria to stress and cardioprotective responsiveness to KATP channel activation, mitochondrial membrane potential modulation and inhibition of mitochondrial permeability transition pore will also be determined. This comprehensive analysis of the effect of aging on atrial biology is of high clinical significance. Recognition of aging-associated specific functional defects and its rectification by homeostatic pathway modulation will identify targets that can be selected to reinstate the lost protective responsiveness of the senescent heart and thereby development of strategies to limit adverse atrial structural and electrical remodeling with stress and disability with aging. Public Health Relevance: This study will identify specific defects that underlie loss of cardioprotection in the elderly and identify therapeutic targets to prevent, slow or reverse changes that increase vulnerability of the aging atria to injury. This information is of high public health interest, since cardiovascular diseases continue to be the leading cause of disability in the elderly.

描述（由申请人提供）：衰老会增加心血管功能障碍，但衰老人类心肌应激敏感性增加的分子基础仍不清楚。尽管随着年龄的增长，心房电和结构异常的患病率呈指数增长，但对心房的了解尤其少。我们对衰老啮齿动物的初步研究表明，与年龄相关的内源性心脏保护丧失与线粒体能量储备的减少和心肌将应激信号转导为保护反应的能力破坏有关。然而，由于防御机制缺陷，衰老的啮齿动物心脏可以通过调节线粒体膜电位和激活 ATP 敏感钾 (KATP) 通道来得到保护。与衰老相关的内源性心脏保护反应的丧失是否也发生在老年人心房中尚不清楚。在初步研究中，使用成人和老年患者的心房组织，在衰老的心脏中证明了调节线粒体能量和心脏保护途径的基因（包括人类 KATP 通道代谢解码器亚基）明显的转录下调。我们假设衰老的人类心房对损伤的脆弱性增加是由于与衰老相关的能量稳态减弱导致心肌对能量衰竭、钙超载和应激期间氧化剂增加敏感。我们建议定义与年龄相关的i）人类心房能量稳态的变化及其对压力耐受性的功能影响； ii) 与年龄相关的能量学变化的机制，重点关注将能源生产与能源传感和利用途径联系起来的途径； iii) 通过调节应激反应稳态途径，拯救衰老的人类心房肌细胞和线粒体免受应激引起的损伤。这些目标将通过使用在手术中从成人（35-55岁）和老年（65-85岁）患者身上获得的人类右心耳来实现。拟议研究的新颖之处在于从相同的人类心房组织中获取功能、分子、遗传和蛋白质组信息，以表征基线和应激条件下心脏能量学、代谢和心脏保护信号、蛋白质-蛋白质相互作用和细胞生理学的与年龄相关的变化。还将确定有关老年人和成人心房对应激的敏感性以及对 KATP 通道激活、线粒体膜电位调节和线粒体通透性转换孔抑制的心脏保护反应的信息。这种对衰老对心房生物学影响的综合分析具有很高的临床意义。认识到与衰老相关的特定功能缺陷并通过稳态通路调节进行纠正，将确定可以选择的目标来恢复衰老心脏失去的保护性反应性，从而制定限制因压力和残疾而导致的不良心房结构和电重塑的策略老化。公共健康相关性：这项研究将确定导致老年人心脏保护丧失的具体缺陷，并确定治疗目标，以预防、减缓或逆转导致老化心房易受损伤的变化。这一信息具有很高的公共卫生意义，因为心血管疾病仍然是老年人残疾的主要原因。