Molecular features and cell composition of left-dominant arrhythmogenic cardiomyopathy reveals key pathways and therapeutic targets

IF 2.3 4区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS
Yiqi Zhao , Mengda Xu , Xiumeng Hua , Yuan Chang , Yixuan Sheng , Dan Shan , Ningning Zhang , Xiao Chen , Jiangping Song
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引用次数: 0

Abstract

Background

Arrhythmogenic cardiomyopathy (ACM) is a myocardial disorder characterized by arrhythmias and an increased risk of sudden cardiac death, particularly in left-dominant arrhythmogenic cardiomyopathy (LACM), which primarily affects the left ventricle. This study aims to elucidate the cellular and molecular mechanisms underlying LACM by performing an in-depth single-nucleus RNA sequencing (snRNA-seq) analysis to identify key transcriptional signatures and pathways involved in the disease's pathogenesis.

Method

Human heart samples were collected from five patients undergoing heart transplantation due to ACM and from four healthy donors. Single nuclei were isolated from myocardial tissues and subjected to snRNA-seq using the 10 × Genomics Chromium platform. Data were processed and analyzed to identify distinct cell populations and their differentially expressed genes. Immunofluorescence staining was used to validate key findings.

Result

The snRNA-seq analysis revealed an increased proportion of fibroblasts and adipocytes in the left ventricles of LACM patients, suggesting a cellular basis for the fibrofatty remodeling observed in the disease. Key cell populations, including cardiomyocytes (CMs), fibroblasts (Fbs), and adipocytes (Adipo), were identified with distinct transcriptional profiles. We identified a disease-associated cardiomyocyte subpopulation (CM1) characterized by upregulation of fibrosis-, metabolism-, and stress-related markers, indicating transcriptional remodeling processes involved in LACM. The Fb subgroup Fb1 was characterized by genes involved in the PI3K-AKT signaling pathway. Adipocyte subpopulations exhibited gene expression features reflecting adaptation to the cardiac pathological environment, including markers associated with extracellular matrix remodeling and metabolic stress.
Immunofluorescence staining validated the high expression of key markers of LACM patients.

Conclusion

This study provides a cellular and molecular characterization of LACM, identifying key pathways and transcriptional signatures that contribute to the disease's pathogenesis. These findings enhance our understanding of LACM and offer potential targets for therapeutic intervention.
左显性心律失常性心肌病的分子特征和细胞组成揭示了关键途径和治疗靶点。
背景:心律失常性心肌病(ACM)是一种以心律失常和心源性猝死风险增加为特征的心肌疾病,尤其是左显性心律失常性心肌病(LACM),主要影响左心室。本研究旨在通过深入的单核RNA测序(snRNA-seq)分析来阐明LACM的细胞和分子机制,以确定参与该疾病发病机制的关键转录特征和途径。方法:取5例因ACM进行心脏移植的患者和4例健康供者的心脏标本。从心肌组织中分离出单核,使用10 × Genomics Chromium平台进行snrna测序。对数据进行处理和分析,以确定不同的细胞群及其差异表达的基因。免疫荧光染色用于验证关键发现。结果:snRNA-seq分析显示,LACM患者左心室成纤维细胞和脂肪细胞比例增加,提示该疾病中观察到的纤维脂肪重塑有细胞基础。关键细胞群,包括心肌细胞(CMs)、成纤维细胞(Fbs)和脂肪细胞,被鉴定出具有不同的转录谱。我们发现了一个疾病相关的心肌细胞亚群(CM1),其特征是纤维化、代谢和应激相关标志物上调,表明LACM涉及转录重塑过程。Fb亚群Fb1以参与PI3K-AKT信号通路的基因为特征。脂肪细胞亚群表现出反映心脏病理环境适应性的基因表达特征,包括与细胞外基质重塑和代谢应激相关的标志物。免疫荧光染色证实了LACM患者关键标志物的高表达。结论:本研究提供了LACM的细胞和分子特征,确定了促进该疾病发病的关键途径和转录特征。这些发现增强了我们对LACM的理解,并为治疗干预提供了潜在的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cardiovascular Pathology
Cardiovascular Pathology 医学-病理学
CiteScore
7.50
自引率
2.70%
发文量
71
审稿时长
18 days
期刊介绍: Cardiovascular Pathology is a bimonthly journal that presents articles on topics covering the entire spectrum of cardiovascular disease. The Journal''s primary objective is to publish papers on disease-oriented morphology and pathogenesis from clinicians and scientists in the cardiovascular field. Subjects covered include cardiovascular biology, prosthetic devices, molecular biology and experimental models of cardiovascular disease.
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