Human Senescence and Cardioprotection

人类衰老与心脏保护

• 批准号: 8301029
• 负责人: ARSHAD JAHANGIR
• 金额: $ 15.81万
• 依托单位: AURORA HEALTH CARE, INC.
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301029
• 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; Defect; Defense Mechanisms; Development; Disease Progression; 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; 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; public health relevance; 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）：衰老会增加心血管障碍，但衰老人类心肌的应激敏感性增加的分子基础仍然未知。尽管心房电气和结构异常的患病率呈指数增长，但对心房的了解尤其鲜为人知。我们在衰老啮齿动物的初步研究表明，与线粒体能量储量的减少以及心肌能力的破坏相关的内源性心脏保护的丧失以及将压力信号转导向保护性反应的心肌能力的破坏。但是，防御机制缺乏防御机制，可以通过调节线粒体膜电位和ATP敏感钾（KATP）通道的激活来保护衰老的啮齿动物心脏。在老年人心房中，内源性心脏保护反应的衰老相关丧失是否也不清楚。在试点研究中，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的独特转录下调，包括人KATP代谢解码器亚基，包括人类KATP的代谢解码器亚基。我们假设，衰老的人心房对损伤的脆弱性增加是由于与能量稳态相关的衰老衰减导致的，这使心肌对高能衰竭，钙超负荷和压力期间的氧化剂增加敏感。我们建议定义与年龄相关的i）人类心房中能量稳态的变化及其对压力耐受性的功能后果； ii）基于年龄相关的能量变化的机制，其重点是将能量产生与能量传感和利用途径联系起来的途径； iii）通过调节压力响应式稳态途径，从应激诱导的损伤中拯救了衰老的人心房肌细胞和线粒体。这些目标将使用成人（35 - 55年）和老年人（65 - 85年）患者手术期间的人权心房附属物实现。拟议的研究的新颖性是从相同的人心房组织获得功能，分子，遗传和蛋白质组学信息，以表征与年龄相关的心脏能量，代谢和心脏保护信号，蛋白质 - 蛋白质相互作用，基础和应力条件下的细胞生理学的变化。还将确定人类老化和成年心房对KATP通道激活，线粒体膜电位调节以及抑制线粒体通透性过渡孔的敏感性的信息。对衰老对心房生物学影响的全面分析具有很高的临床意义。识别与衰老相关的特定功能缺陷及其通过稳态途径调节的整流将确定可以选择恢复衰老心脏的保护性反应性的目标，从而制定策略，从而限制不良心房结构和电气重塑，并随着压力和残疾而随着衰老而进行压力和残疾。公共卫生相关性：本研究将确定老年人心脏保护损失的特定缺陷，并确定预防，缓慢或反向变化的治疗靶标，以增加衰老心房对受伤的脆弱性。该信息具有很高的公共卫生利益，因为心血管疾病仍然是老年人残疾的主要原因。

项目成果

Strain Echocardiography and LQTS Subtypes: Mechanical Alterations in an Electrical Disorder.

应变超声心动图和 LQTS 亚型：电障碍中的机械改变。

• DOI: 10.1016/j.jcmg.2015.03.001
• 发表时间: 2015
• 期刊: JACC. Cardiovascular imaging
• 作者: Jahangir,Arshad;Jain,Renuka
• 通讯作者: Jain,Renuka

Cardiac subsarcolemmal and interfibrillar mitochondria display distinct responsiveness to protection by diazoxide.

• DOI: 10.1371/journal.pone.0044667
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Holmuhamedov EL;Oberlin A;Short K;Terzic A;Jahangir A
• 通讯作者: Jahangir A

TGF-β1-mediated differentiation of fibroblasts is associated with increased mitochondrial content and cellular respiration.

• DOI: 10.1371/journal.pone.0123046
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Negmadjanov U;Godic Z;Rizvi F;Emelyanova L;Ross G;Richards J;Holmuhamedov EL;Jahangir A
• 通讯作者: Jahangir A

Circulating Biomarkers Predictive of Postoperative Atrial Fibrillation.

• DOI: 10.1097/crd.0000000000000059
• 发表时间: 2016-03
• 期刊: Cardiology in review
• 影响因子: 2.1
• 作者: Turagam MK;Mirza M;Werner PH;Sra J;Kress DC;Tajik AJ;Jahangir A
• 通讯作者: Jahangir A

Chamber-specific differences in human cardiac fibroblast proliferation and responsiveness toward simvastatin.

人心脏成纤维细胞增殖和对辛伐他汀反应的腔室特异性差异。

• DOI: 10.1152/ajpcell.00056.2016
• 发表时间: 2016
• 期刊: American journal of physiology. Cell physiology
• 作者: Rizvi,Farhan;DeFranco,Alessandra;Siddiqui,Ramail;Negmadjanov,Ulugbek;Emelyanova,Larisa;Holmuhamedov,Alisher;Ross,Gracious;Shi,Yang;Holmuhamedov,Ekhson;Kress,David;Tajik,AJamil;Jahangir,Arshad
• 通讯作者: Jahangir,Arshad