NF-κB激活对心房颤动犬自主神经重构机制的影响及他汀的保护作用

Atrial autonomic nervous remodeling (ANR), electrical remodeling and structural remodeling play important roles in the pathogenesis of atrial fibrillation (AF). Based on our preliminary studies, inflammation may promote electrical remodeling and structural remodeling of AF, and inflammation may upregulate both the nerve growth factor (NGF) and growth associated protein-43(GAP-43), which are critical for cardiac autonomic nerve sprouting and remodeling. Therefore, we assume that, activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor, may induce the up-regulation of inflammatory cytokines, then upregulate the expression of NGF and GAP-43, promoting the ANR in AF. This study aims to explore the influence of NF-κB activation on ANR of AF and possible protection of statin, which acting as anti-inflammatory drug. To confirm the above hypothesis, the atrial-tachypacing-AF models were established. First, the cardiac electrophysiological study, immunohistochemistry and molecular biology methods are used to determine the role of NF-κB activation in the consequent cytokines upregulation with atrial autonomic remodeling. Second, the specific inhibitor of NF-κB and statin was used to demonstrate the inflammatory response in ANR. Last, through upregulation and inhibition of NF-κB, to test the influence of inflammatory cytokines on neural and ionic distribution density and cellular signal transduction. This study will provide evidence of a potential upstream target for AF therapy.

心房自主神经重构(ANR)、电学及结构重构是房颤发生发展的重要机制。我们前期证实炎症促进房颤的电学及结构重构，而炎症因子能上调神经重构关键因素神经生长因子（NGF）和生长相关蛋白-43（GAP-43）表达。由此我们推测，ANR发生的机制可能与促进房颤心肌重构的炎症上游调控因子NF-κB通过放大心肌炎症反应上调心肌NGF和GAP-43表达有关。本项目旨在探讨NF-κB激活对房颤ANR机制的影响及抗炎药物他汀可能的保护作用。首先经心房快速起搏建立房颤犬模型，从整体和组织水平应用心内电生理检查、免疫组化及分子生物学技术分析房颤时NF-κB及其下游激活的炎症因子与ANR程度的相关性；其次，用NF-κB特异性抑制剂PDTC和他汀抑制NF-κB探讨炎性反应在ANR的作用；最后在细胞水平通过上调和抑制NF-κB研究炎性因子对神经因子和离子流分布密度的作用及信号通路。本项目可能为房颤防治提供新的干预靶点。

心房自主神经重构(ANR)、电学及结构重构是房颤发生发展的重要机制。我们前期证实炎症促进房颤的电学及结构重构，而炎症因子能上调神经重构关键因素神经生长因子（NGF）和生长相关蛋白-43（GAP-43）表达。由此我们推测，ANR发生的机制可能与促进房颤心肌重构的炎症上游调控因子NF-κB通过放大心肌炎症反应上调心肌NGF和GAP-43表达有关。本项目首先建立房颤犬模型，系统分析了房颤的重构、炎症及自主神经重构情况。从细胞层面探讨了NF-κB在房颤自主神经重构的机制；总结了房颤患者血浆内皮素-1和C反应蛋白的关系，评价了非房颤患者内皮系统激活和炎症反应的相关性；系统总结了房颤患者酒精对心房基质重构的影响，以及对导管消融的疗效；对功能性二尖瓣反流房颤患者心房结构重构特点及对导管消融结果的影响进行总结；对非瓣膜性房颤患者的内皮功能和卒中风险进行探讨；分析了房颤导管消融早期使用非Vit K口服抗凝药（NOAC）依从性的影响因素；对房颤患者心房肌组织及细胞代谢的甲基化和乙酰化机制进行了分析，深化了对房颤机制的理解，也为后续进一步对房颤机制研究奠定了基础。目前已发表国内外研究论文4篇，其中SCI论文1篇，中文核心期刊3篇；SCI审稿阶段论文2篇；授权实用新型专利1项，申请发明专利1项；获得北京市科学技术奖（自然科学奖）二等奖1项。