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

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.

总结 心房颤动（AF）是最常见的具有临床意义的心律失常，并且其常常导致 毁灭性的结果。由于目前的治疗往往是无效的，因此迫切需要一种新的治疗方法。 提高了对房颤机制的理解，并提出了治疗房颤的新策略。 将氧化应激与AF的发病机制和进展联系起来，但针对这些因素的上游治疗 过程是无效的。脂质醛是氧化应激相关损伤的主要成分， 产生的最具反应性的产物，异evuglandins（IsoLGs），几乎瞬间与蛋白质反应， 导致功能障碍。二羰基清除剂已经被开发出来，在它们被释放之前， 可以与生物靶点相互作用。使用这些工具，IsoLGs最近被确定为神经内分泌的关键介质。 血管紧张素II介导的高血压和阿尔茨海默病。氧化应激疾病也与 蛋白质毒性或由错误折叠的蛋白质引起的细胞功能障碍。在淀粉样疾病中，比如阿尔茨海默氏症， 类磷脂寡聚体（PAO）现在被认为是与以下相关的主要细胞毒性物质： 疾病进展。值得注意的是，IsoLG显著加速淀粉样蛋白的PAO形成。基于 根据我们的初步数据，这项提议的目的是检验这样一种假设，即异长链烷烃和聚烯烃都是 促进AF易感性的生物学相关介质，使其成为潜在的治疗靶点。 我们已经获得了令人信服的初步数据，以支持IsoLGs和PAO是 AF底物：PAO通常在人心房中检测到，具有心房利钠素的纤维生成蛋白 肽（ANP）的主要成分，它们与高血压有关; IsoLGs和PAO形成于 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、肥胖症和家族性AF;清除IsoLGs以减少心房颤动的有益作用。 PAO和AF负荷。此外，与家族性AF相关的ANP突变形式显著增强了 的细胞毒性ANP寡聚体，这些PAO积累在小鼠的心房模拟人类疾病。的 第一个目的是检验在高血压和肥胖中，氧化应激介导的IsoLGs促进 心房细胞损伤和房颤易感性。目的2将检验突变型ANP寡聚体改变心房肌细胞的 肌细胞稳态产生AF易感性，它们促进氧化应激/IsoLG形成， 可以前馈以延续病理过程。最后，目标3将检验以下假设： 高血压，与氧化应激相关的其他AF风险因素也与IsoLGs的积累相关 和/或细胞毒性PAO，支持它们在人类疾病中的作用。所提出的研究具有重大意义， 考虑到IsoLG和PAO不仅可以提供氧化应激之间的共同机制联系， 蛋白毒性、常见临床风险因素和AF，而且是预防和/或治疗AF的新治疗靶点。 治疗这种常见的心律失常。