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Exosomal
let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axisExosomal
let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis- 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 - Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Vol. 25, Issue 5, Pages: 422-437(2024)
- Affiliations：
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
- Funds：
DOI：10.1631/jzus.B2300077
CLC：- CSTR：
Published： 15 May 2024 ，
Received： 07 February 2023 ，
Revised： 29 June 2023 ，
李欣,胡亚楠,吴越廷等.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[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(05):422-437.
Xin LI, Yanan HU, Yueting WU, et al. 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 (Biomedicine & Biotechnology) 25(5):422-437(2024)李欣,胡亚楠,吴越廷等.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[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(05):422-437. DOI： 10.1631/jzus.B2300077.
Xin LI, Yanan HU, Yueting WU, et al. 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 (Biomedicine & Biotechnology) 25(5):422-437(2024) DOI： 10.1631/jzus.B2300077.
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-exo
let-7a-5p
mimic
对CVB3诱导的铁死亡的抑制作用高于hucMSCs-exo
mimic 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Fe
2+
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。
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-exo
let-7a-5p
mimic
on CVB3-induced ferroptosis was higher than that of hucMSCs-exo
mimic 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 Fe
2+
increased. In conclusion
the
se 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
外泌体Let-7a-5pSMAD2柯萨奇病毒B3（CVB3）铁死亡
Keywords
ExosomeLet-7a-5pMothers against decapentaplegic homolog 2 (SMAD2)Coxsackievirus B3 (CVB3)Ferroptosis
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