New Molecular Target for Cardiac Aging

心脏衰老的新分子靶点

• 批准号: 8985498
• 负责人: Heng-Jie Cheng
• 金额: $ 31.78万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985498
• 关键词: ATP2A2; Address; Adrenergic Agents; Adrenergic Agonists; Adrenergic Antagonists; Adrenergic Receptor; Affect; Age; Aging; Agonist; Animals; Attention; Biological Availability; Biological Preservation; Blood Vessels; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Cell Size; Cell physiology; Chronic; Congestive Heart Failure; Coupling; Cyclic AMP; Cytochrome c Oxidase Subunit IV; Disease; Down-Regulation; Effectiveness; Elderly; Equilibrium; Exercise; Gelatinase B; Gene Expression; Gene Targeting; Glean; Grant; Heart; Homeostasis; Human; Indium; Inflammatory; Isoproterenol; Knock-out; Knowledge; Lead; Left; Measurement; Measures; Mediating; Mitochondrial Proteins; Molecular; Molecular Analysis; Molecular Target; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Myocardial dysfunction; Nitrates; Nitric Oxide; Norepinephrine; Outcome; Oxidation-Reduction; Pathologic; Pathway interactions; Performance; Peroxonitrite; Physiological; Physiology; Prevalence; Prevention; Property; Protein Isoforms; Proteins; Public Health; Receptor Signaling; Receptor Up-Regulation; Regulation; Research Personnel; Rest; Reticulum; Risk; Role; Ryanodine Receptor Calcium Release Channel; Signal Pathway; Signal Transduction; Stress; Structure; Sympathetic Nervous System; System; Testing; Tissues; Up-Regulation; Ventricular; Wild Type Mouse; Work; adrenergic; age effect; aged; beta-adrenergic receptor; clinically significant; cytochrome c; desensitization; electric impedance; hemodynamics; human NOS2A protein; innovation; insight; interdisciplinary approach; mitochondrial uncoupling protein 3; mortality; new therapeutic target; nitration; novel; oxidant stress; phospholamban; pressure; prevent; public health relevance; receptor density; receptor expression; response; sex

 DESCRIPTION (provided by applicant): This application addresses one of the most fundamental aspects of the effect of aging on cardiovascular function, cardiac aging (CA), and congestive heart failure (CHF). Myocardial aging leads to a progressive decline in cardiac function and ß-adrenergic reserve, which increases the risk of CHF and cardiac morbidity. However, the precise mechanism is unclear. This grant investigates the role and mechanism of the signaling pathway mediated by ß3-adrenergic receptors (ARs) in CA. This pathway has negative effects on cardiac function, but has received limited attention in age-associated cardiac dysfunction. Our recent observations have shown that aging up-regulates cardiac ß3-ARs with enhanced ß3-AR-mediated negative modulations on cardiac function, [Ca2+]i regulation and the effectiveness of ß-adrenergic signaling. Chronic ß3-AR stimulation triggers up-regulation of cardiac inducible nitric oxide synthase (iNOS) and its uncoupling. Oxidant stress from iNOS uncoupling further aggravates cardiac dysfunction. These aging-induced alterations were prevented in ß3-AR knockout (ß3KO) aged mice and were reversed through treatment with a ß3-antagonist (ANT) in wild- type (WT) aged mice, suggesting that alteration of cardiac ß3-AR may be a critical element in the development of CA. We will test the Central Hypothesis that up-regulation of cardiac ß3-AR signaling, as a consequence of aging-induced sympathetic overdrive (with elevated catecholamine levels), not only contributes to, but is an important cause of CA. Thus, antagonizing ß3-AR with a selective ß3-ANT would be effective on the prevention and treatment of CA, leading to a normalization of ß3-AR expression and Ca2+ cycling/handling of cardiomyocytes, while contributing to the preservation of ß1-and ß2-ARs and ventricular arterial de-stiffening in the elderly. Studies will be conducted in age-matched and sex-matched SPF young and aged mice of control wild-type (WT), ß3KO, ß3TG/ß3KO and aged WT with and without chronic ß3-ANT treatment. Three specific aims are proposed to study intact animals, isolated cardiomyocytes, and molecular mechanisms. Using an integrative and multidisciplinary approach, serial and simultaneous measurements of LV structure alterations, LV and myocyte as well as vascular functional performance, cardiac calcium handling, gene expression, redox state, NOS coupling status, and neurohormonal activation in these animals will characterize the alterations of ß3-AR-mediated functional responses with related molecular and cellular signal transductions of CA and define the role and mechanism of ß3-ANT therapy in CA. This work will unravel aging-induced alterations at multiple levels (heart, cellular, sub-cellular, and molecular) and glean crucial insights concerning how the balance of ß3- , ß1-, and ß2-ARs and the altered ß3-AR-mediated nitric oxide signaling affects cardiovascular performance in aging. This is a highly innovative proposal, and the outcomes will have a high impact, enhancing our understanding of the pivotal mechanisms of CA and CHF and may lead to new therapeutic targets for this important problem. These studies may also provide the rationale for the study of ß3-blockers in human CA.

 描述（由申请人提供）：本申请涉及衰老对心血管功能、心脏衰老（CA）和充血性心力衰竭（CHF）影响的最基本方面之一。心肌老化导致心脏功能和β-肾上腺素能储备的进行性下降，这增加了CHF和心脏病发病率的风险。然而，确切的机制尚不清楚。本基金研究CA中β 3-肾上腺素能受体（AR）介导的信号通路的作用和机制。该通路对心脏功能有负面影响，但在与年龄相关的心功能不全中受到的关注有限。我们最近的观察表明，衰老上调心脏β 3-AR，增强β 3-AR介导的对心脏功能、[Ca 2 +]i调节和β-肾上腺素能信号传导的有效性的负性调节。慢性β 3-AR刺激触发心脏诱导型一氧化氮合酶（iNOS）的上调及其解偶联。iNOS解偶联的氧化应激进一步加重心功能障碍。这些衰老诱导的改变在β 3-AR敲除（β 3 KO）老年小鼠中被阻止，并且在野生型（WT）老年小鼠中通过β 3-拮抗剂（ANT）治疗被逆转，这表明心脏β 3-AR的改变可能是CA发展中的关键因素。我们将检验中心假说，即心脏β 3-AR信号的上调，作为衰老诱导的交感神经兴奋（伴随升高的儿茶酚胺水平）的结果，不仅有助于CA，而且是CA的重要原因。因此，用选择性β 3-ANT拮抗β 3-AR将有效预防和治疗CA，导致β 3-AR表达和心肌细胞的Ca 2+循环/处理正常化，同时有助于老年人中β 1-和β 2-AR的保存和心室动脉去硬化。研究将在对照野生型（WT）、β 3 KO、β 3 TG/β 3 KO和有和无慢性β 3-ANT治疗的老年WT的年龄匹配和性别匹配的SPF年轻和老年小鼠中进行。三个具体的目标，提出了研究完整的动物，分离的心肌细胞，和分子机制。使用综合和多学科的方法，连续和同时测量LV结构改变、LV和肌细胞以及血管功能性能、心脏钙处理、基因表达、氧化还原状态、NOS偶联状态，这些动物中的神经激素激活将表征β 3-AR的改变，介导的功能反应与CA的相关分子和细胞信号转导，并确定β 3-ANT治疗CA的作用和机制。这项工作将在多个层面（心脏，细胞，亚细胞和分子）揭示衰老引起的变化。 并收集关于β 3-、β 1-和β 2-AR的平衡以及β 3-AR介导的一氧化氮信号改变如何影响衰老中的心血管性能的重要见解。这是一个高度创新的建议，其结果将产生很大的影响，增强我们对CA和CHF关键机制的理解，并可能为这一重要问题带来新的治疗靶点。这些研究也可能为β 3-阻滞剂在人类CA中的研究提供理论基础。