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（由应用程序提供）：此申请地址衰老对心血管功能，心脏老化（CA）和充血性心力衰竭（CHF）的影响最基本的方面之一。心肌老化导致心脏功能和β-肾上腺素储备的逐步下降，这增加了CHF和心脏发病率的风险。但是，确切的机制尚不清楚。该赠款研究了CA中由ß3-肾上腺素能（ARS）介导的信号通路的作用和机制。该途径对心脏功能有负面影响，但在与年龄相关的心脏功能障碍方面受到了有限的关注。我们最近的观察结果表明，老化对心脏功能，[Ca2+] I调节和β-肾上腺素能信号传导的有效性增强的ß3AR介导的负面调制会增强心脏ß3-AR。慢性ß3-ar刺激会触发心脏诱导的一氧化氮合酶（INOS）及其解偶联的上调。 iNOS解偶联的氧化应激进一步加剧了心脏功能障碍。这些衰老引起的改变在β3-AR敲除（ß3KO）老年小鼠中得到了预防，并通过用β3-抗抗酸剂（ANT）在野生型（WT）老年小鼠中进行治疗，这表明心脏ß3-AR的改变可能是CA发展的关键元素。我们将检验以下中心假设：由于衰老引起的交感神经超速驱动（降低了儿茶酚胺水平升高），心脏ß3-ar信号传导的上调不仅有助于CA。这是用选择性ß3-ant拮抗ß3-ar对CA的预防和处理有效，从而导致ß3-AR表达和心脏体系细胞的Ca2+循环/处理方法的归一化，同时有助于保存ß1-and-ass和ß2-ARS和ß2-ARS和cartriculin Cartriculin and Cartricular antertrical anteritial De-NETEFENS在旧旧的中。研究将以对照野生型（WT），ß3KO，ß3TG/ß3KO和老年WT的年龄匹配和性匹配的SPF年轻小鼠和老年小鼠进行，并没有慢性ß3-抗治疗。提出了三个特定的目标来研究完整的动物，孤立的心肌细胞和分子机制。 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 ß3-ant疗法在CA中的作用和机制。这项工作将在多个水平（心脏，细胞，细胞和分子）下揭示衰老诱导的改变 以及有关ß3-，ß1-和ß2-ARS以及改变的ß3AR介导的一氧化氮信号的平衡如何影响心血管表现的关键见解。这是一项高度创新的建议，结果将产生很大的影响，从而增强了我们对CA和CHF关键机制的理解，并可能导致这一重要问题的新治疗靶标。这些研究还可能为研究人类CA的研究提供了基本原理。