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On-line Access: 2024-05-10

Received: 2023-02-07

Revision Accepted: 2023-06-29

Crosschecked: 2024-05-10

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Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Yang LIU

0000-0003-4626-3618

Hanmin LIU

0000-0002-4633-911X

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Journal of Zhejiang University SCIENCE B 2024 Vol.25 No.5 P.422-437

http://doi.org/10.1631/jzus.B2300077


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


Author(s):  Xin LI, Yanan HU, Yueting WU, Zuocheng YANG, Yang LIU, Hanmin LIU

Affiliation(s):  Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu 610041, China; more

Corresponding email(s):   cyggly@126.com, liuhm@scu.edu.cn

Key Words:  Exosome, Let-7a-5p, Mothers against decapentaplegic homolog 2 (SMAD2), Coxsackievirus B3 (CVB3), Ferroptosis


Xin LI, Yanan HU, Yueting WU, Zuocheng YANG, Yang LIU, Hanmin LIU. Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis[J]. Journal of Zhejiang University Science B, 2024, 25(5): 422-437.

@article{title="Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis",
author="Xin LI, Yanan HU, Yueting WU, Zuocheng YANG, Yang LIU, Hanmin LIU",
journal="Journal of Zhejiang University Science B",
volume="25",
number="5",
pages="422-437",
year="2024",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2300077"
}

%0 Journal Article
%T Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis
%A Xin LI
%A Yanan HU
%A Yueting WU
%A Zuocheng YANG
%A Yang LIU
%A Hanmin LIU
%J Journal of Zhejiang University SCIENCE B
%V 25
%N 5
%P 422-437
%@ 1673-1581
%D 2024
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2300077

TY - JOUR
T1 - Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis
A1 - Xin LI
A1 - Yanan HU
A1 - Yueting WU
A1 - Zuocheng YANG
A1 - Yang LIU
A1 - Hanmin LIU
J0 - Journal of Zhejiang University Science B
VL - 25
IS - 5
SP - 422
EP - 437
%@ 1673-1581
Y1 - 2024
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2300077


Abstract: 
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 effect of hucMSCs-exolet-7a-5p mimic on CVB3-induced ferroptosis was higher than that of hucMSCs-exomimic NC (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 Fe2+ 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.

人脐带间充质干细胞来源的外泌体let-7a-5p通过SMAD2/ZFP36信号轴减轻柯萨奇病毒B3诱导的心肌细胞铁死亡

李欣1,2,3,4,5,胡亚楠6,吴越廷1,2,3,4,5,杨作成6,刘洋1,2,3,4,5,刘瀚旻1,2,3,4,5
1四川大学华西第二医院小儿呼吸免疫科,中国成都市,610041
2四川大学妇幼出生缺陷及相关疾病教育部重点实验室,中国成都市,610041
3国家卫生健康委员会时间生物学重点实验室(四川大学),中国成都市,610041
4四川大学华西第二医院与复旦大学生命科学学院肺发育及相关疾病联合实验室,华西第二医院华西妇女儿童健康研究所,中国成都市,610041
5四川大学华西第二医院四川省出生缺陷临床研究中心,中国成都市,610041
6中南大学湘雅三医院儿科,中国长沙市,410013
摘要:病毒性心肌炎(VMC)是儿童和青少年最常见的获得性心脏病之一。其发病机制尚不明确,且缺乏有效的治疗方法。本研究旨在探讨外泌体减轻柯萨奇病毒B3(CVB3)诱导的心肌细胞(CMCs)铁死亡的调控通路。我们用CVB3诱导小鼠VMC模型和细胞模型,使用心脏超声心动图、左室射血分数(LVEF)和左室短轴缩短率(LVFS)评价心功能。在CVB3诱导的VMC小鼠中,我们观察到小鼠心功能不全和铁死亡相关指标(谷胱甘肽过氧化酶4(GPX4)、谷胱甘肽(GSH)和丙二醛(MDA))的表达失调。然而,人脐带间充质干细胞来源的外泌体(hucMSCs-exo)可以恢复CVB3引起的改变。Let-7a-5p富集于hucMSCs-exo中,且hucMSCs-exolet-7a-5p mimic对CVB3诱导的铁死亡的抑制作用高于hucMSCs-exomimic NC。在VMC组中,SMAD2表达升高,而ZFP36表达降低。Let-7a-5p靶向SMAD2信使RNA(mRNA),且SMAD2蛋白与ZFP36蛋白直接相互作用。沉默SMAD2和过表达ZFP36均可抑制铁死亡相关指标的表达。同时,与oe-NC+let-7a-5p mimic组比较,oe-SMAD2+let-7a-5p mimic组中的GPX4、溶质载体家族7成员11(SLC7A11)和GSH水平降低,而MDA、活性氧(ROS)和Fe2+水平升高。综上所述,这些数据表明铁死亡可以通过介导SMAD2的表达来调节。HucMSCs来源的exo-let-7a-5p可以通过介导SMAD2促进ZFP36的表达,进一步抑制CMCs的铁死亡,从而缓解CVB3诱导的VMC。

关键词:外泌体;Let-7a-5p;SMAD2;柯萨奇病毒B3(CVB3);铁死亡

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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