Novel Pathophysiological Targets in Atrial Fibrillation Susceptibility

心房颤动易感性的新病理生理学目标

• 批准号: 9921464
• 负责人: KATHERINE T MURRAY
• 金额: $ 47.61万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921464
• 关键词: Aging; Aldehydes; Alzheimer' s Disease; Amyloid; Amyloidosis; Angiotensin II; Arrhythmia; Atrial Fibrillation; Atrial Natriuretic Factor; Binding; Biological; Cardiac; Cardiac Surgery procedures; Cardiovascular system; Cells; Clinical Trials; Data; Disease; Disease Progression; Electrophysiology (science); Familial atrial fibrillation; Functional disorder; General Population; Generations; Genes; Goals; Health; Heart Atrium; Hereditary Disease; Homeostasis; Human; Hypertension; Injury; Interruption; Knowledge; Link; Lipid Peroxidation; Lipids; Mediating; Mediator of activation protein; Microscopic; Mission; Modeling; Molecular Target; Morbidity - disease rate; Mus; Muscle Cells; Mutation; Obesity; Outcome; Oxidative Stress; Pathogenesis; Pathologic Processes; Patients; Peptides; Predisposition; Prevention; Process; Proteins; Public Health; Reactive Oxygen Species; Research; Risk Factors; Role; Structure; Testing; Tissues; United States National Institutes of Health; base; cell injury; clinical practice; clinical risk; clinically significant; common treatment; cytotoxic; human disease; improved; in vivo Model; misfolded protein; mortality; mouse model; mutant; new therapeutic target; novel; novel strategies; peptide A; prevent; proteotoxicity; success; therapeutic target; therapy design; tool; Aging; Aldehydes; Alzheimer' s Disease; Amyloid; Amyloidosis; Angiotensin II; Arrhythmia; Atrial Fibrillation; Atrial Natriuretic Factor; Binding; Biological; Cardiac; Cardiac Surgery procedures; Cardiovascular system; Cells; Clinical Trials; Data; Disease; Disease Progression; Electrophysiology (science); Familial atrial fibrillation; Functional disorder; General Population; Generations; Genes; Goals; Health; Heart Atrium; Hereditary Disease; Homeostasis; Human; Hypertension; Injury; Interruption; Knowledge; Link; Lipid Peroxidation; Lipids; Mediating; Mediator of activation protein; Microscopic; Mission; Modeling; Molecular Target; Morbidity - disease rate; Mus; Muscle Cells; Mutation; Obesity; Outcome; Oxidative Stress; Pathogenesis; Pathologic Processes; Patients; Peptides; Predisposition; Prevention; Process; Proteins; Public Health; Reactive Oxygen Species; Research; Risk Factors; Role; Structure; Testing; Tissues; United States National Institutes of Health; base; cell injury; clinical practice; clinical risk; clinically significant; common treatment; cytotoxic; human disease; improved; in vivo Model; misfolded protein; mortality; mouse model; mutant; new therapeutic target; novel; novel strategies; peptide A; prevent; proteotoxicity; success; therapeutic target; therapy design; tool

SUMMARY Atrial fibrillation (AF) is the most common cardiac arrhythmia of clinical significance, and it often results in devastating outcomes. Because current treatment is frequently ineffective, there is a critical need for an improved understanding of the mechanisms causing AF and novel strategies to treat it. Abundant evidence has linked oxidative stress to the pathogenesis and progression of AF, yet upstream therapy to target these processes has been ineffective. Lipid aldehydes are a major component of oxidative stress-related injury, and the most reactive products generated, isolevuglandins (IsoLGs), react almost instantaneously with proteins to cause dysfunction. Dicarbonyl scavengers have been developed that preemptively bind IsoLGs before they can interact with biologic targets. Using these tools, IsoLGs were recently identified as critical mediators in angiotensin II-mediated hypertension and Alzheimer's disease. Diseases of oxidative stress are also linked to proteotoxicity, or cellular dysfunction caused by misfolded proteins. In amyloid diseases like Alzheimer's, preamyloid oligomers (PAOs) are now recognized to be the primary cytotoxic species that correlates with disease progression. Notably, IsoLGs markedly accelerate PAO formation for amyloidogenic proteins. Based on our preliminary data, the goal of this proposal is to test the hypotheses that both IsoLGs and PAOs are biologically-relevant mediators that promote AF susceptibility, making them potential therapeutic targets. We have acquired compelling preliminary data to support the concept that IsoLGs and PAOs are drivers of the AF substrate: PAOs are commonly detected in human atrium, with the fibrillogenic protein atrial natriuretic peptide (ANP) a major component, and they associate with hypertension; IsoLGs and PAOs are formed in cellular and in vivo models associated with AF susceptibility, including rapidly-stimulated atrial cells, hypertension, obesity, and familial AF; and there is a beneficial effect of scavenging IsoLGs to reduce atrial PAO and AF burden. Moreover, a mutant form of ANP linked to familial AF markedly enhances the formation of cytotoxic ANP oligomers, and these PAOs accumulate in the atria of mice modeling the human disease. The first Aim will test the hypothesis that in hypertension and obesity, oxidative stress-mediated IsoLGs promote atrial cell injury and AF susceptibility. Aim 2 will test the hypothesis that mutant ANP oligomers alter atrial myocyte homeostasis to generate AF susceptibility, and they promote oxidative stress/IsoLG formation that can feed-forward to perpetuate the pathologic process. Finally, Aim 3 will test the hypothesis that in addition to hypertension, other AF risk factors linked to oxidative stress are also associated with accumulation of IsoLGs and/or cytotoxic PAOs, supporting their role in human disease. The proposed studies have major significance, given that IsoLG and PAOs may provide not only common mechanistic links between oxidative stress, proteotoxicity, common clinical risk factors, and AF, but also novel therapeutic targets in the prevention and/or treatment of this common arrhythmia.

概括 心房颤动（AF）是最常见的临床意义心律失常，并且通常导致 毁灭性的结果。由于当前治疗通常是无效的，因此非常需要 对导致AF和新型策略进行治疗的机制的理解得以提高。大量证据有 将氧化应激与AF的发病机理和进展相关联，但在上游疗法以靶向这些 过程无效。脂质醛是氧化应激相关损伤的主要组成部分，并且 产生的最具反应性产物，Isolevuglandins（Isalgs），几乎立即与蛋白质反应 引起功能障碍。已经开发了DiCarbonyl的清道夫，可以在他们之前先发行二手 可以与生物学靶标相互作用。使用这些工具，最近将隔离识别为关键调解人 血管紧张素II介导的高血压和阿尔茨海默氏病。氧化应激的疾病也与 蛋白质毒素引起的蛋白质毒性或细胞功能障碍。在像阿尔茨海默氏症这样的淀粉样蛋白疾病中 现在被认为是与py虫的主要细胞毒性物种相关的主要细胞毒性物种 疾病进展。值得注意的是，分离菌明显加速了PAO形成的淀粉样蛋白。基于 在我们的初步数据上，该提案的目的是测试伊斯兰和鲍斯的假设 与生物学相关的介质，可促进AF敏感性，使其具有潜在的治疗靶标。 我们已经获得了引人入胜的初步数据，以支持伊斯兰和宝斯是驱动因素的概念 AF底物：PAO通常在人庭中检测到，具有原纤维蛋白心房纳替雷剂 肽（ANP）是主要成分，它们与高血压相关；在 与AF易感性相关的细胞和体内模型，包括快速刺激的心房细胞， 高血压，肥胖和家庭AF；清除隔离以减少房屋有有益的效果 PAO和AF负担。此外，与家族性AF相关的ANP的突变形式显着增强了形成 细胞毒性ANP低聚物，这些PAO在对人类疾病进行建模的小鼠的心房中积累。这 第一个目标将检验以下假设，即在高血压和肥胖症中，氧化应激介导的分离株促进 心房细胞损伤和AF敏感性。 AIM 2将测试突变体ANP寡聚物改变心房的假设 心肌稳态产生AF的敏感性，并促进氧化应激/孤立的形成 可以向前喂食以使病理过程永存。最后，AIM 3还将检验以下假设。 高血压，与氧化应激相关的其他AF危险因素也与分离菌的积累有关 和/或细胞毒性PAO，支持其在人类疾病中的作用。拟议的研究具有重要意义， 鉴于Iselg和Paos不仅可以提供氧化应激之间的共同机械联系， 蛋白质毒性，常见的临床危险因素和AF，以及预防和/或预防的新型治疗靶标 治疗这种常见心律失常。