Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis  

作　　者：Xin LI Yanan HU Yueting WU Zuocheng YANG Yang LIU Hanmin LIU 

机构地区：[1]Department of Pediatric Pulmonology and Immunology,West China Second University Hospital,Sichuan University,Chengdu 610041,China [2]Key Laboratory of Birth Defects and Related Diseases of Women and Children(Sichuan University),Ministry of Education,Chengdu 610041,China [3]NHC Key Laboratory of Chronobiology(Sichuan University),Chengdu 610041,China [4]The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital,Sichuan University and School of Life Sciences of Fudan University,West China Institute of Women and Children's Health,West China Second University Hospital,Sichuan University,Chengdu 610041,China [5]Sichuan Birth Defects Clinical Research Center,West China Second University Hospital,Sichuan University,Chengdu 610041,China [6]Department of Pediatrics,the Third Xiangya Hospital,Central South University,Changsha 410013,China

出　　处：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》2024年第5期422-437,共16页浙江大学学报（英文版）B辑（生物医学与生物技术）

基　　金：supported by the China Postdoctoral Science Foundation(No.2022M712252);the Natural Science Foundation of Sichuan Province,China(No.2023NSFSC1634).

摘　　要：Viral myocarditis(VMC)is one of the most common acquired heart diseases in children and teenagers.However,its pathogenesis is still unclear,and effective treatments are lacking.This study aimed to investigate the regulatory pathway by which exosomes alleviate ferroptosis in cardiomyocytes(CMCs)induced by coxsackievirus B3(CVB3).CVB3 was utilized for inducing the VMC mouse model and cellular model.Cardiac echocardiography,left ventricular ejection fraction(LVEF),and left ventricular fractional shortening(LVFS)were implemented to assess the cardiac function.In CVB3-induced VMC mice,cardiac insufficiency was observed,as well as the altered levels of ferroptosis-related indicators(glutathione) peroxidase 4(GPX4),glutathione(GSH),and malondialdehyde(MDA).However,exosomes derived from human umbilical cord mesenchymal stem cells(hucMSCs-exo)could restore the changes caused by CVB3 stimulation.Let-7a-5p was enriched in hucMSCs-exo,and the inhibitory ffect of hucMSCs-exoa-ie-pmimo on CVB3-induced ferroptosis was higher than that of hucMSCs-exommie N(NC:negative control).Mothers against decapentaplegic homolog 2(SMAD2)increased in the VMC group,while the expression of zinc-finger protein 36(ZFP36)decreased.Let-7a-5p was confirmed to interact with SMAD2 messenger RNA(mRNA),and the SMAD2 protein interacted directly with the ZFP36 protein.Silencing SMAD2 and overexpressing ZFP36 inhibited the expression of ferroptosis-related indicators.Meanwhile,the levels of GPX4,solute carrier family 7,member 11(SLC7A11),and GSH were lower in the SMAD2 overexpression plasmid(oe-SMAD2)+let-7a-5p mimic group than in the oe-NC+let-7a-5p mimic group,while those of MDA,reactive oxygen species(ROS),and Fe^(2+)increased.In conclusion,these data showed that ferroptosis could be regulated by mediating SMAD2 expression.Exo-let-7a-5p derived from hucMSCs could mediate SMAD2 to promote the expression of ZFP36,which further inhibited the ferroptosis of CMCs to alleviate CVB3-induced VMC.

关 键 词：Exosome Let-7a-5p Mothers against decapentaplegic homolog 2(SMAD2) Coxsackievirus B3(CVB3) Ferroptosis 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]