Preamyloid Oligomers and Susceptibility to Atrial Fibrillation

前淀粉样蛋白寡聚物和心房颤动的易感性

• 批准号: 8443864
• 负责人: KATHERINE T MURRAY
• 金额: $ 36.69万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443864
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloidosis; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Arrhythmia; Atrial Fibrillation; Atrial Natriuretic Factor; Atrial Tachycardia; Boxing; Canis familiaris; Cardiac Surgery procedures; Cells; Chronic; Clinical; Complex; Data; Degenerative Disorder; Deposition; Development; Disease; Employee Strikes; Epidemic; Exhibits; General Population; Generations; Genes; Goals; Heart Atrium; Heart failure; Hour; Human; In Vitro; Incidence; Inflammation; Ion Channel; Link; Morbidity - disease rate; Mutation; Neurodegenerative Disorders; Oxidative Stress; Pathogenesis; Persons; Play; Population; Postoperative Period; Predisposition; Process; Proteins; Research; Risk; Risk Factors; Role; Sampling; Stretching; Stroke; Testing; Tissues; Up-Regulation; base; common treatment; heart function; heart rhythm; improved; in vivo; lifetime risk; mortality; mutant; new therapeutic target; novel; novel strategies; oxidant stress; prevent; protein misfolding; public health relevance; response

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common cardiac arrhythmia, resulting in substantial morbidity and mortality. An important risk factor for developing AF is age, with a lifetime risk of 1 in 6 for the condition. The incidence of AF is increasing in epidemic proportion as the US population ages, and currently available treatment is often ineffective. The clinical course of AF is typically progressive, due to electrical and structural remodeling in the atria with rapid stimulation that increases arrhythmia susceptibility. Oxidative stress and inflammation play an important role in generating the AF substrate and promoting this remodeling process. Recently, we showed that atrial cells rapidly stimulated in culture undergo remodeling very similar to that observed in human AF. Importantly, transcriptional profiling in paced cells exhibited striking concordance with changes seen in vivo. Unexpectedly, we observed conserved transcriptional upregulation in proteins involved in amyloidosis, a process associated with protein misfolding and deposition in multiple neurodegenerative diseases, notably Alzheimer's disease. Substantial evidence indicates that the toxic species in these disorders are soluble preamyloid oligomer intermediates, rather than the mature fibrillar, amyloid-positive deposits. Indeed, our preliminary data demonstrate striking accumulation of preamyloid oligomers in rapidly-paced atrial cells, with similar results in experimental and human AF. Taken together, these data form a strong rationale for the proposed studies. The goal of this proposal is to test the hypothesis that atrial preamyloid oligomers are pathophysiologically linked to the development of AF in humans. In Specific Aim 1, human atrial samples obtained during routine cardiac surgery at multiple centers will be used to examine the relationship of preamyloid oligomer formation to age, the risk of postoperative AF, and established AF in humans. Indicators of oxidative stress will also be investigated in these samples. In Specific Aim 2, we will explore the effects of potent antioxidant/anti-inflammatory compounds that are also known to inhibit soluble oligomer formation, on the generation of atrial preamyloid oligomers in response to rapid stimulation in vitro and during experimental AF. Atrial natriuretic peptide (ANP) is known to form amyloid fibrils, and it is present in isolated atrial amyloidosis, a process that increases with aging in humans. Recently, mutations in ANP were causally linked to familial AF. In Specific Aim 3, we will determine whether these ANP mutations promote the formation of preamyloid oligomers as a potential mechanism to increase AF susceptibility. The proposed studies have substantial significance, since preamyloid oligomers may not only provide a mechanistic link between oxidative stress, aging, and AF, but they may also provide a novel therapeutic target in the treatment of this common and difficult to treat arrhythmia.

描述（由申请人提供）：心房颤动（AF）是最常见的心律失常，导致大量的发病率和死亡率。发生房颤的一个重要风险因素是年龄，一生中患房颤的风险为六分之一。随着美国人口老龄化，房颤发病率呈流行比例上升，目前可用的治疗方法往往无效。房颤的临床过程通常是进行性的，因为心房的电和结构重构伴随着快速刺激，增加了心律失常的易感性。氧化应激和炎症在AF底物的产生和促进这一重塑过程中起重要作用。最近，我们发现在培养中快速刺激的心房细胞经历的重塑与在人类房颤中观察到的非常相似。重要的是，节律细胞的转录谱显示出与体内观察到的变化惊人的一致性。出乎意料的是，我们观察到与淀粉样变性有关的蛋白质的保守转录上调，淀粉样变性是多种神经退行性疾病（尤其是阿尔茨海默病）中蛋白质错误折叠和沉积的一个过程。大量证据表明，这些疾病中的有毒物质是可溶性淀粉样蛋白前寡聚体中间体，而不是成熟的纤维状淀粉样蛋白阳性沉积物。事实上，我们的初步数据表明，在快节奏的心房细胞中，淀粉样蛋白前寡聚物显著积累，在实验和人类心房纤颤中也有类似的结果。总之，这些数据为提出的研究提供了强有力的理论依据。本提案的目的是验证心房前淀粉样蛋白低聚物与人类房颤发展的病理生理学联系的假设。在Specific Aim 1中，在多个中心的常规心脏手术中获得的人类心房样本将用于检查前淀粉样蛋白低聚物形成与年龄、术后房颤风险和人类房颤的关系。氧化应激指标也将在这些样品中进行研究。在特异性目标2中，我们将探索有效的抗氧化/抗炎化合物的作用，这些化合物也被称为抑制可溶性低聚物的形成，在体外和实验性心房颤动期间对快速刺激的心房前淀粉样蛋白低聚物的产生。心房利钠肽（ANP）已知可形成淀粉样蛋白原纤维，并且存在于孤立的心房淀粉样变性中，这一过程随着人类年龄的增长而增加。最近，ANP突变与家族性房颤有因果关系。在Specific Aim 3中，我们将确定这些ANP突变是否促进淀粉样蛋白前寡聚物的形成，作为增加房颤易感性的潜在机制。所提出的研究具有重大意义，因为淀粉样蛋白前寡聚物可能不仅提供氧化应激、衰老和房颤之间的机制联系，而且还可能为治疗这种常见且难以治疗的心律失常提供新的治疗靶点。