IgE调节心脏重塑的分子机制研究

Heart failure is a life-threatening disease. Clarifying its risk factors and the involved pathogenic mechanisms is essential for preventing and controlling heart failure. The development of cardiac fibrosis is an important pathologic process in cardiac remodeling. Our early cohort data and animal experiments have established that IgE is associated with heart failure, which may be correlated with IgE regulated cardiac fibroblast dysfunction. Our previous results showed that the serum IgE was markedly increased in cardiac dysfunction patients and three heart failure mice models, and myocardial fibrosis were significantly deteriorated in heart tissue of heart failure mice model. Blocking IgE-FcεR1 pathway by knockout of FcεR1 was able to relieve cardiac fibrosis. Besides, IgE significantly reduced miR486 expression in myocardial fibroblasts. Therefore, we hypothesize that: IgE may promote cardiac fibrosis by down-regulating miR486 expression in cardiac fibroblasts; IgE-MiR486 may be a new diagnostic and therapeutic target for heart failure. To test the above hypothesis, we are planning to do the following research: 1) to elucidate the molecular mechanism by which IgE-MiR486 regulates cardiac remodeling and promotes heart failure; 2) to investigate the possibility of alleviating cardiac fibrosis by blocking IgE-miR486 signaling pathway; 3) to explore the possibility of IgE-MiR486 as a diagnostic marker in clinical samples. After all, this study is designed to verify the role of IgE in regulating heart fibrosis, which will provide a theoretical basis for discovering new risk factors, pathogenetic mechanism, and therapeutic target or strategy to manage heart failure.

心衰导致死亡的重要原因，阐明心衰的危险因素及发病机制是心衰防控的关键，心脏纤维化是心脏重塑导致心衰的重要病理过程。本项目前期人群数据和动物模型实验确立IgE与心衰相关，这可能与IgE调节的心脏成纤维细胞功能障碍有关。实验证明：心衰病人及三种心衰模型小鼠血浆中IgE增加，心脏纤维化显著; 敲除FcεR1减轻纤维化程度; IgE显著下调成纤维细胞miR486表达. 由此推断：IgE介导的心脏成纤维细胞miR486的下降促进心脏纤维化；IgE-miR486可能成为心衰诊疗新靶点。本项目拟联合应用人群数据，动物模型及分子细胞实验探索：1）IgE-miR486调节心脏纤维化的分子机制；2）阻断IgE-miR486信号通路，减缓心脏纤维化的可能性；3）应用临床大数据，探索IgE-miR486作为心衰诊断标记物的可能性。本项目将为明确心衰的新危险因素、发病机理和诊疗靶点提供理论依据。

IgE是过敏反应的一种重要介质，临床上血清高IgE不仅见于过敏性疾病，也见于多种非过敏疾病中。大量研究报道：IgE的升高与冠心病、动脉粥样硬化、腹主动脉瘤等多种心血管疾病相关。FcεR1是IgE的高亲和力受体，表达于多种细胞表面，如肥大细胞、嗜碱性粒细胞、巨噬细胞、CD4+T细胞、平滑肌细胞、内皮细胞等。IgE-FcεR1信号存在于以上多种细胞，且以往的研究表明，该信号可通过介导炎症反应和血管重构参与促进腹主动脉瘤和动脉粥样硬化的发生发展。但是，IgE在心衰中的作用尚不清晰，本项目深入探究了IgE与心衰的相关性及其在心衰中的功能和作用机制。.本项目借助心衰动物模型（AngII心衰动物模型，TAC心衰动物模型，过敏性哮喘-心衰动物模型）和体外实验（WT和FcɛR1敲除的心肌成纤维细胞实验）深入揭示了：1）IgE-miR-486-5p调节心脏纤维化进而促进心衰的分子机制。利用心脏成纤维细胞模型和心衰动物模型进一步确认了miR-486-5p为IgE的下游分子，明确了IgE介导miR-486-5p下调进而上调靶基因SMAD1 SMAD2上调纤维化基因Collagen1/3促进纤维化的分子机制。2）借助FcɛR1敲除小鼠、IgE/ FcɛR1抗体以及miR-486-5p模拟物封闭阻断IgE-miR486通路，研究其减缓心脏纤维化的可能性；3）应用临床样本分析并明确了IgE和miR-486-5p作为心衰诊断标记物的可能性。本项目丰富了心衰发病的新危险因素及机制，明确了IgE作为心衰诊疗新靶点的潜能，这将为心衰的临床诊疗特别是过敏合并高IgE心衰患者的诊疗有重要的临床指导意义。.相关研究成果发表在2021年Circulation，Theranostics杂志，2022年Translational Research，Cardiovascular Research杂志。