Functional Microdomains in the Heart's Pacemaker: A New Dimension of Cardiac Remodeling

心脏起搏器中的功能微域：心脏重塑的新维度

• 批准号: 9883641
• 负责人: Alexey V Glukhov
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883641
• 关键词: Action Potentials; Adenosine Monophosphate; Affect; Area; Arrhythmia; Atrial Flutter; Bradycardia; Cardiac; Cardiovascular Diseases; Caveolae; Caveolins; Cell membrane; Cellular Structures; Cholesterol; Complex; Coupling; Cyclic AMP; Data; Dimensions; Down-Regulation; Electrophysiology (science); Ensure; Fibrosis; Functional disorder; Generations; Heart; Heart Atrium; Heart Diseases; Heart Rate; Heart failure; Hyperactive behavior; Implant; Integral Membrane Protein; Ion Channel; Knock-out; Mediating; Membrane; Membrane Microdomains; Mus; Muscle; Muscle Cells; Operative Surgical Procedures; Pacemakers; Patients; Periodicity; Pharmacology; Phosphorylation; Play; Protein Isoforms; Proteins; Public Health; Regulation; Research; Role; Ryanodine Receptors; Scaffolding Protein; Secondary to; Signal Transduction; Signaling Molecule; Sinoatrial Node; Sphingolipids; Structure; Surface; System; Tachycardia; Treatment Efficacy; Work; biophysical properties; caveolin-3; cost; design; heart dimension/size; human old age (65+); implantation; interstitial; nodal myocyte; non-Native; novel; prevent; protein expression; protein protein interaction; restoration; statistics; subcellular targeting; sudden cardiac death; voltage

ABSTRACT Sinoatrial node (SAN) dysfunction (SND) is associated with abnormal impulse formation and propagation in the SAN. Recent estimates suggest that >75,000 new cases of SND occur in the U.S. every year and that this number will more than double by 2060. At present, surgical implantation of permanent pacemakers remains the most efficient treatment of SND which, however, is limited when compared with pharmacologic therapy and costs $2 billion annually in the U.S. Contemporary evidence suggests an emerging role of compartmentalized remodeling (i.e. associated with distinct, spatially-confined micro-domains) of pacemaker proteins in SND. Our studies and others have demonstrated that the proteins involved in pacemaking activity are associated with specific membrane microdomains, caveolae, i.e., small (50–100 nm) invaginations of the plasma membrane enriched by cholesterol, sphingolipids and scaffolding proteins caveolin-3 (Cav3). Here, we propose that Cav3 organizes specialized pacemaker signaling complexes providing functional coupling between the sarcolemmal proteins (referred to as a surface ‘membrane clock’) and subcellular Ca2+ machinery (referred to as an ‘intracellular Ca2+ clock’). We hypothesize that disruption in subcellular targeting of pacemaker proteins and associated signaling molecules upon structural remodeling of the SAN, may affect their biophysical properties and neurohormonal regulation as well as protein-protein interactions within the pacemaker signaling complex disturbing rhythmic generation of action potentials and thus contributing to the pathophysiology of the SND. This research introduces a novel concept of electrophysiological changes resulting from alternations in the subcellular compartmentalization of signaling complexes following structural remodeling. This extends beyond the classical concept of electrical remodeling, according to which dysfunction can be explained by straightforward increases or decreases in protein expression alone, and adds a new dimension to cardiovascular disease. This research will open completely new avenues for sophisticated and more effective therapeutic approaches targeted at preventing the degradation of cardiac cytoarchitecture.

摘要 窦房结功能障碍(SND)与心脏电刺激的异常形成和传播有关。 山姆。最近的估计表明，美国每年发生75,000例新的SND病例，而这 到2060年，这一数字将增加一倍以上。目前，永久起搏器的外科植入仍然是 最有效的SND治疗，然而，与药物治疗和成本相比是有限的 美国每年20亿美元。当代证据表明，分割的作用正在显现 SND起搏蛋白的重构(即与不同的、空间受限的微域相关)。我们的 研究和其他研究表明，参与起搏活动的蛋白质与 特殊的膜微域，小凹，即质膜的小内陷(50-100 nm) 富含胆固醇、鞘脂和支架蛋白小窝蛋白-3(Cav3)。在这里，我们建议Cav3 组织专门的起搏器信号复合体，提供肌膜之间的功能耦合 蛋白质(称为表面‘膜钟’)和亚细胞钙机制(称为 “细胞内钙离子时钟”)。我们假设起搏器蛋白亚细胞靶向的中断和 窦房结结构重塑时的相关信号分子可能会影响其生物物理性质 和神经激素调节以及起搏信号复合体内的蛋白质-蛋白质相互作用 扰乱动作电位的节律性产生，从而导致SND的病理生理学。这 研究引入了一个新的概念，即由亚细胞变化引起的电生理变化 结构重塑后信号复合体的区域化。这超出了古典的范畴 电重构的概念，根据该概念，功能障碍可以用直接的增加来解释 或仅在蛋白质表达方面减少，并为心血管疾病增加了一个新的维度。这项研究 将为针对以下目标的复杂和更有效的治疗方法开辟全新的途径 防止心肌细胞构筑的退化。