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科研成果: “Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction”(王婧)
作者: 时间:2021-03-25 微信分享:
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导读: 王婧课题组于202139日在Circulation杂志发表研究论文Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction”。该研究工作发现了血清高IgE水平与心脏重塑的相关性;揭示IgE-FcεR1信号直接作用于心脏固有细胞(心肌细胞和成纤维细胞),促进心脏重塑新机制;证明了阻断IgE-FcεR1信号对心脏重塑保护作用,为心力衰竭提供诊疗了新靶点。

文章链接:https://www.ahajournals.org/doi/epub/10.1161/CIRCULATIONAHA.120.047852

 


 

1. IgE-FcεR1促进心肌重构模式图

 

心力衰竭是由各种心脏结构或功能性疾病引起心室充盈和泵血功能受损,最终造成心排量降低,外周灌注不足的一组临床综合征,是各种心脏疾病发展的终末阶段。心衰在全球范围内患病率较高,发达国家成年人心衰患病率为1%-2%70岁以上人群的患病率≥10%2003年的流行病学调查发现我国成人心衰患病率为0.9%,随着人口老龄化,以及高血压、糖尿病等慢性病发病率的上升、人们生活方式、饮食习惯的改变,心衰的患病率还会逐年攀升。并且心衰患者的病死率和住院率仍维持在较高水平,不仅严重威胁了患者的生命健康及和生活质量,也给公共卫生造成了极大的负担。因此,心衰的防治是当前国内外心血管领域中研究的重点,除了加强心衰患者的综合管理以外,对于新的防治靶点的寻找也具有十分重要的意义。免疫球蛋白是浆细胞产生的一类具有抗体活性的蛋白质,是介导体液免疫的重要效应分子。免疫球蛋白可以分为IgGIgAIgMIgDIgE五类,其中IgE主要参与针对特定过敏原的免疫反应。多项研究表明,IgE的升高与腹主动脉瘤、动脉粥样硬化、动脉粥样硬化性心脏病等多种心血管疾病相关。

王婧团队通过对心衰患者血管紧张素IIAngII)灌注和主动脉弓缩窄术(TAC)诱导的心衰小鼠血清免疫球蛋白的筛查发现,心衰患者和小鼠血清IgE水平显著高于健康对照组,且与心功能的损伤呈现正相关。在心衰的心脏组织中,IgE高亲和力受体FcεR1表达增加。阻断IgE信号通路(使用FcεR1敲除鼠,IgE中和抗体IgE单克隆抗体奥马珠单抗)能够显著减轻TAC/AngII诱导的心脏重塑和心功能下降进一步的研究阐明IgE-FcεR1介导心脏重塑分子机制:发现IgE直接作用于心肌细胞和成纤维细胞的FcεR1通过激活TGF-β以及其下游信号通路促进心肌细胞肥大和心脏纤维化

这项研究证明了IgE-FcεR1信号在促进病理性心脏重塑和心功能障碍中的重要作用,揭示IgE-FcεR1促进心脏重塑机制,赋予了IgE 及其受体在疾病机制研究中的新角色,拓展了对心脏重塑发病机制的认识,心脏重塑和心力衰竭的临床干预提供了靶点。

【摘要】Immunoglobulin E (IgE) belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor (FcεR1) in pathological cardiac remodeling and heart failure are unknown. Here, we observed that serum IgE levels were significantly elevated in patients with heart failure as well as in 2 mouse cardiac disease models induced by chronic pressure overload via transverse aortic constriction and chronic angiotensin II infusion. Interestingly, FcεR1 expression levels were also significantly upregulated in failing hearts from human and mouse. Blockade of the IgE-FcεR1 pathway by FcεR1 knockout alleviated transverse aortic constriction– or angiotensin II–induced pathological cardiac remodeling or dysfunction. Anti-IgE antibodies (including the clinical drug omalizumab) also significantly alleviated angiotensin II–induced cardiac remodeling. Bone marrow transplantation experiments indicated that IgE-induced cardiac remodeling was mediated through non–bone marrow–derived cells. FcεR1 was found to be expressed in both cardiomyocytes and CFs. In cultured rat cardiomyocytes, IgE-induced cardiomyocyte hypertrophy and hypertrophic marker expression were abolished by depleting FcεR1. In cultured rat CFs, IgE-induced CF activation and matrix protein production were also blocked by FcεR1 deficiency. RNA sequencing and signaling pathway analyses revealed that transforming growth factor-β may be a critical mediator, and blocking transforming growth factor-β indeed alleviated IgE-induced cardiomyocyte hypertrophy and cardiac fibroblast activation in vitro. These findings suggest that IgE induction plays a causative role in pathological cardiac remodeling, at least partially via the activation of IgE-FcεR1 signaling in cardiomyocytes and CFs. Therapeutic strategies targeting the IgE-FcεR1 axis may be effective for managing IgE-mediated cardiac remodeling.

该研究由中国医学科学院基础医学研究所和医学分子生物学国家重点实验室王婧团队联合美国罗彻斯特大学、北京协和医院共同完成。基础医学研究所重点实验室赵红梅副研究员、杨红琴学士、耿驰博士为本文的共同第一作者,王婧研究员、罗彻斯特大学严琛教授为共同通讯作者。此研究获得国家重点研发计划(2019YFA0801800,2019YFA0801700)、国家自然科学基金(81622008,81470579,81800359)、中国医学科学院医学与健康科技创新工程基金(2016I2M-1-006)、北京协和医学院青年基金(3332016048)的资助。北京协和医院郭潇潇副教授参与了此研究项目。

医学分子生物学国家重点实验室