Interrogating early molecular events of doxorubicin-induced cardiotoxicity at single-cell level to identify new cardioprotective agents

心脏毒性 阿霉素 医学 药理学 内科学 化疗
作者
Marco Mergiotti,Yue Qin,Michele Russo,Sam N. Barnett,M Lee,Andreia Machado Miranda,Aydin Huseynov,Sophie Cnudde,Lorenzo Prever,Rebecca Toscano Rivalta,P Haves,Michael Schneider,Emilio Hirsch,Michela Noseda,Alessandra Ghigo
出处
期刊:Cardiovascular Research [Oxford University Press]
卷期号:120 (Supplement_1)
标识
DOI:10.1093/cvr/cvae088.121
摘要

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Leducq Foundation Background Doxorubicin (DOX) is a highly effective chemotherapeutic agent widely used for treating various types of malignancies. Unfortunately, its clinical implication is hampered by cardiotoxic side effects which are responsible for increased mortality among cancer survivors compared to the general population. Preclinical and clinical studies have highlighted potential mechanisms of anthracycline-induced cardiotoxicity (AIC), but the core molecular basis remains largely unknown. More importantly, only a few studies have focused on the characterization of the molecular events that distinguish the early reversible phase of AIC from an advanced and irreversible state of the disease. Aim We aim to provide an unbiased and in-depth profile of early transcriptional changes induced by DOX at single cell resolution, to identify new druggable targets for the development of cardioprotective agents to prevent AIC. Methods Based on our previously established murine model of AIC, BALB/c mice were injected with saline (Vehicle) or DOX (3 weekly injections of 4 mg/kg), and hearts were collected at either 3 days (acute cardiotoxicity) or 6 weeks after the first injection (chronic cardiotoxicity). Nuclei were isolated from frozen hearts for single-nuclei transcriptomic (snRNAseq; 10x Genomics, Chromium Single Cell 3' v3.1). Seurat pipeline was mainly used for downstream bioinformatic analysis. Results Echocardiography revealed DOX-induced systolic dysfunction at 6 weeks, confirming the establishment of AIC. SnRNAseq data from 12 hearts allowed to identify 8 major cell types including cardiomyocytes (CM), endothelial and mural cells, fibroblasts, myeloid cells, B and T lymphocytes and neuronal-like cells. To unravel changes in CM, we performed unbiased subclustering which defined 6 different subpopulations, including a CM_Stressed population, characterized by enrichment of typical cardiac stress markers, such as natriuretic peptide hormone (Nppb) and myosin heavy chain 7 (Myh7). Differential abundance analysis showed enrichment of the CM-Stressed population at both 3 days and 6 weeks, suggesting that DOX drives a transcriptional change toward stress status in CM both at early and late stages of cardiotoxicity. Differential gene expression analysis revealed Golgi associated kinase 1B (Gask1B) to be significantly upregulated at both 3 days and 6 weeks in CM_Stressed. In agreement, preliminary experiments showed that Gask1b gene silencing partially rescued DOX-induced heart dysfunction in zebrafish model and hiPSC-derived CM, identifying Gask1b as a potential new player in DOX cardiotoxicity. Conclusions We generated a single-nucleus dataset of DOX-treated mouse hearts and identified transcriptional changes driven by DOX in CM at early and late stages of the disease. Furthermore, we identified Gask1b gene, whose role in cardiac pathophysiology was previously unappreciated, as a new potential marker and determinant of DOX cardiotoxicity.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
吉小聿发布了新的文献求助20
1秒前
2秒前
2秒前
NexusExplorer应助Ruby采纳,获得10
2秒前
zhijiner发布了新的文献求助10
3秒前
Tolerate完成签到 ,获得积分10
4秒前
5秒前
ruby发布了新的文献求助10
5秒前
刘青秀发布了新的文献求助10
5秒前
6秒前
天天快乐应助小小橙采纳,获得10
6秒前
6秒前
冷酷的夜完成签到,获得积分10
7秒前
8秒前
共享精神应助LQX2141采纳,获得10
8秒前
FF完成签到 ,获得积分10
9秒前
优秀爆米花完成签到,获得积分10
10秒前
duanduan发布了新的文献求助10
10秒前
烂番茄完成签到 ,获得积分10
11秒前
追三发布了新的文献求助10
12秒前
GAO发布了新的文献求助10
12秒前
ccq发布了新的文献求助10
12秒前
0376完成签到,获得积分20
12秒前
13秒前
害羞映容发布了新的文献求助10
14秒前
15秒前
15秒前
16秒前
16秒前
Hello应助自由芷雪采纳,获得10
16秒前
悲伤西米露应助苹果笑寒采纳,获得20
16秒前
16秒前
Lucas应助wang佳俊采纳,获得10
17秒前
17秒前
Ava应助禾晏采纳,获得10
18秒前
18秒前
wxy发布了新的文献求助10
18秒前
李健应助ronll采纳,获得10
18秒前
小小橙发布了新的文献求助10
19秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 700
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Nucleophilic substitution in azasydnone-modified dinitroanisoles 500
不知道标题是什么 500
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3976177
求助须知:如何正确求助?哪些是违规求助? 3520366
关于积分的说明 11202745
捐赠科研通 3256847
什么是DOI,文献DOI怎么找? 1798509
邀请新用户注册赠送积分活动 877704
科研通“疑难数据库(出版商)”最低求助积分说明 806516