Targeting Vascular Leak and Intercalated Disk Nanodomains to Prevent Atrial Fibrillation

摘要 炎症和血管渗漏是几种相关病理的常见表现。 心律不齐。其中包括房颤(AF)，它影响着多达3%的美国人口。 房颤会逐渐恶化，增加中风和心血管疾病的风险。因此，我们 迫切需要新的、机械驱动的治疗房颤的方法。房颤患者血管渗漏的结果 由于血管内皮生长因子等炎性细胞因子水平升高 (血管内皮生长因子)。虽然房颤血管渗漏的血栓形成影响已被广泛认识，但它在房颤中的作用 心律失常的发生机制尚不清楚。血管渗漏和心律失常之间的一个可能联系可能是 是心肌水肿。PI最近的研究表明，水肿扰乱了钠通道 (NaV1.5)插入盘内富含纳米结构域(ID)，减缓心脏搏动 传播，并引发心律失常。在初步研究中，血管内皮生长因子(在 房颤患者的血清)提高了房颤的体外和体内小鼠实验30 几分钟。因此，我们假设细胞因子诱导的血管渗漏促进心脏 水肿，并通过破坏富含NaV1.5的ID纳米结构域而导致房性心律失常。在……里面 在这个项目中，我们将使用尖端工具，包括超分辨率显微镜、3D电子 显微镜和智能膜片钳研究血管结构和功能的影响 房性心动过速的结构和功能的泄漏。此外，我们将利用创新战略 粘附域的多肽模拟物将被用来选择性地调节 不同的ID纳米域。AIM 1将使用这些多肽来研究不同的ID 纳米结构域有助于心房传导，并探索潜在的基本机制 这些结构-功能关系。在新的初步数据中，我们证明了血管内皮生长因子- 诱导的血管漏导致ID纳米结构域肿胀和NaV1.5移位 网站在30分钟内。AIM 2将研究血管内皮生长因子对结构和功能的急性影响- 导致血管渗漏。目标3将使用体外和体内模型来测试保存的效果 血管屏障和/或ID纳米结构域在预防房颤中的作用

ABSTRACT Inflammation and vascular leak are common findings across several pathologies associated with arrhythmias. These include atrial fibrillation (AF), which affects up to 3% of the US population. AF progressively worsens, and increases risk of stroke and cardiovascular disease. Thus, we urgently need novel, mechanistically-driven therapies for AF. Vascular leak in AF patients results from elevated serum levels of inflammatory cytokines such as vascular endothelial growth factor (VEGF). While the thrombogenic impact of vascular leak in AF is widely recognized, its role in arrhythmogenesis remains unclear. One possible link between vascular leak and arrhythmia may be myocardial edema. Recent work by the PI demonstrated that edema disrupts sodium channel (NaV1.5) –rich nanodomains within the intercalated disk (ID), slowing cardiac impulse propagation, and prompting arrhythmias. In preliminary studies, VEGF (at levels found in the serum of AF patients) elevated AF inducibility ex vivo and in vivo mouse experiments within 30 minutes. Therefore, we hypothesize that cytokine-induced vascular leak promotes cardiac edema, and contributes to atrial arrhythmias by disrupting NaV1.5-rich ID nanodomains. In this venture, we will employ cutting edge tools including super-resolution microscopy, 3D electron microscopy, and smart patch clamp to investigate the structural and functional impact of vascular leak on the structure and function of atrial IDs. Furthermore, we will utilize an innovative strategy peptide mimetics of adhesion domains will be used to selectively modulate the structure of different ID nanodomains. Aim 1 will use these peptides to investigate how different ID nanodomains contribute to atrial conduction, and probe fundamental mechanisms underlying these structure-function relationships. In new preliminary data, we demonstrate that VEGF- induced vascular leak induces swelling of ID nanodomains and translocation of NaV1.5 from these sites within 30 minutes. Aim 2 will investigate the acute structural and functional impacts of VEGF- induced vascular leak. Aim 3 will use ex vivo and in vivo models to test the efficacy of preserving the vascular barrier and/or ID nanodomains in preventing AF.