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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 axis.
- Source :
-
Journal of Zhejiang University. Science. B [J Zhejiang Univ Sci B] 2024 May 15; Vol. 25 (5), pp. 422-437. - Publication Year :
- 2024
-
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 <superscript>let-7a-5p</superscript> <superscript>mimic</superscript> on CVB3-induced ferroptosis was higher than that of hucMSCs-exo <superscript>mimic NC</superscript> (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 <superscript>2+</superscript> 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.
- Subjects :
- Animals
Humans
Male
Mice
Coxsackievirus Infections pathology
Enterovirus B, Human physiology
Myocarditis drug therapy
Phospholipid Hydroperoxide Glutathione Peroxidase metabolism
Smad2 Protein metabolism
Umbilical Cord cytology
Exosomes metabolism
Ferroptosis drug effects
Mesenchymal Stem Cells chemistry
MicroRNAs pharmacology
Myocytes, Cardiac pathology
Signal Transduction
Subjects
Details
- Language :
- English; Chinese
- ISSN :
- 1862-1783
- Volume :
- 25
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of Zhejiang University. Science. B
- Publication Type :
- Academic Journal
- Accession number :
- 38725341
- Full Text :
- https://doi.org/10.1631/jzus.B2300077