Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a therapeutic target for arrhythmogenic right ventricular cardiomyopathy.
Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a therapeutic target for arrhythmogenic right ventricular cardiomyopathy.
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供体和终末期心力衰竭患者的单细胞RNA测序将NLRP 3鉴定为致瘤性右心室心肌病的治疗靶点
DOI：
10.1186/s12916-023-03232-8
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发表时间：
2024-01-08
期刊：
影响因子：
9.3
通讯作者：
Song, Jiangping
中科院分区：
文献类型：
--
作者：
Fu, Mengxia;Hua, Xiumeng;Shu, Songren;Xu, Xinjie;Zhang, Hang;Peng, Zhiming;Mo, Han;Liu, Yanyun;Chen, Xiao;Yang, Yicheng;Zhang, Ningning;Wang, Xiaohu;Liu, Zirui;Yue, Guangxin;Hu, Shengshou;Song, Jiangping
扩张可能是第一个右心室的变化，并加速了危险的室性快速性心律失常和心力衰竭的进展，对致心律失常的右心室心肌病（ARVC）的患者，但右心室扩张的治疗仍然有限。对8名研究参与者的血液和双心室心肌进行单细胞RNA测序（scRNA-seq），包括6名ARVC终末期心力衰竭患者和2名正常对照。然后深入分析ScRNA-seq数据，包括聚类注释，细胞比例计算以及细胞发育轨迹和相互作用的表征。对我们的单细胞数据和已发表的基于全基因组关联研究的数据的综合分析提供了对ARVC心律失常表型的细胞特异性贡献的见解。桥粒芯糖蛋白2（Dsg 2）mut/mut小鼠用作ARVC模型以验证药物干预对鉴定的细胞簇的治疗效果。ARVC的右心室富含CCL 3+促炎性巨噬细胞和TNMD+成纤维细胞。成纤维细胞在ARVC中优先受影响，与ARVC相关的扰动与那些存在于与心律失常相关的遗传变异中的扰动重叠。促炎性巨噬细胞与成纤维细胞强烈相互作用。Nod样受体蛋白3（NLRP 3）是一种主要由CCL 3+促炎性巨噬细胞和几种其他骨髓亚群表达的转录因子，其药理学抑制可显著减轻Dsg 2 mut/mut小鼠（ARVC小鼠模型）的右心室扩张和功能障碍。这项研究提供了一个全面的分析谱系特异性变化的血液和心肌从ARVC患者在一个单一的细胞分辨率。药理学抑制NLRP 3可预防ARVC小鼠右心室扩张和功能障碍。在线版本包含补充材料，可通过10.1186/s12916-023-03232-8获得。
Dilation may be the first right ventricular change and accelerates the progression of threatening ventricular tachyarrhythmias and heart failure for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), but the treatment for right ventricular dilation remains limited. Single-cell RNA sequencing (scRNA-seq) of blood and biventricular myocardium from 8 study participants was performed, including 6 end-stage heart failure patients with ARVC and 2 normal controls. ScRNA-seq data was then deeply analyzed, including cluster annotation, cellular proportion calculation, and characterization of cellular developmental trajectories and interactions. An integrative analysis of our single-cell data and published genome-wide association study-based data provided insights into the cell-specific contributions to the cardiac arrhythmia phenotype of ARVC. Desmoglein 2 (Dsg2)mut/mut mice were used as the ARVC model to verify the therapeutic effects of pharmacological intervention on identified cellular cluster. Right ventricle of ARVC was enriched of CCL3+ proinflammatory macrophages and TNMD+ fibroblasts. Fibroblasts were preferentially affected in ARVC and perturbations associated with ARVC overlap with those reside in genetic variants associated with cardiac arrhythmia. Proinflammatory macrophages strongly interact with fibroblast. Pharmacological inhibition of Nod-like receptor protein 3 (NLRP3), a transcriptional factor predominantly expressed by the CCL3+ proinflammatory macrophages and several other myeloid subclusters, could significantly alleviate right ventricular dilation and dysfunction in Dsg2mut/mut mice (an ARVC mouse model). This study provided a comprehensive analysis of the lineage-specific changes in the blood and myocardium from ARVC patients at a single-cell resolution. Pharmacological inhibition of NLRP3 could prevent right ventricular dilation and dysfunction of mice with ARVC. The online version contains supplementary material available at 10.1186/s12916-023-03232-8.
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