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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Mesenchymal stem-derived exosomes enhance therapeutic benefits of exercise in isoproterenol-induced myocardial ischemia: Targeting ERK and Akt/mTOR signaling
Asmaa M ShamsEldeen, Manar M AbdElalim, Nahed S Mohamed, Marwa M AbdelRahman, Samaa S Kamar, Dina H AbdelKader, Samar H Elsharkawy, Laila A Rashed, Salwa S Faisal, Walla’a A Osman, Asmaa M Selmy
Asmaa M ShamsEldeen, Department of Physiology, Cairo University, Cairo 30411, Egypt
Manar M AbdElalim, Nahed S Mohamed, Marwa M AbdelRahman, Asmaa M Selmy, Department of Physiology, Faculty of Medicine, Cairo University, Cairo 30411, Egypt
Samaa S Kamar, Department of Histology, Cairo University, Cairo 30411, Egypt
Samaa S Kamar, Department of Histology, Armed Forces College of Medicine, Cairo 11766, Al Qāhirah, Egypt
Dina H AbdelKader, Department of Histology, Kasr Al-Ainy Faculty of Medicine, Cairo 30411, Egypt
Samar H Elsharkawy, Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Giza 12613, Al Jīzah, Egypt
Laila A Rashed, Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo 30411, Egypt
Salwa S Faisal, Department of Biochemistry and Molecular Biology, Suez Canal University, Ismailia 41511, Egypt
Walla’a A Osman, Department of Pharmacology, Kasr Al-Ainy Faculty of Medicine, Cairo University, Cairo 30411, Al Qāhirah, Egypt
Co-corresponding authors: Asmaa M ShamsEldeen and Samaa S Kamar.
Author contributions: ShamsEldeen AM, AbdElalim MM, Mohamed NS, AbdelRahman MM, Kamar SS, and Selmy AM designed and coordinated the study; AbdElalim MM, AbdelRahman MM, Osman WA, and Selmy AM performed the experiments; ShamsEldeen AM, AbdElalim MM, Mohamed NS, AbdelRahman MM, Kamar SS, AbdelKader DH, Elsharkawy SH, Rashed LA, Faisal SS, Osman WA, and Selmy AM acquired, analyzed and interpreted the data; AbdelRahman MM, Kamar SS, Faisal SS, Osman WA, and Selmy AM wrote the manuscript draft; ShamsEldeen AM, Mohamed NS, AbdelRahman MM, Kamar SS, and Selmy AM reviewed and edited the final manuscript version; ShamsEldeen AM and Kamar SS contributed equally to this manuscript and are co-corresponding authors. All authors approved the final version of the article.
Institutional animal care and use committee statement: The current study was approved by the Institutional Animal Care and Use Committee of Cairo University (Approval No. CU/III/F/59/20).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available. All data generated or analyzed during this study are included in this published article and its supplementary information file.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Asmaa M ShamsEldeen, MD, Assistant Professor, Department of Physiology, Cairo University, Al-Saray Street, El Manial, Cairo 30411, Egypt.
asmaa82shamseldeen@gmail.com
Received: May 26, 2025
Revised: June 19, 2025
Accepted: September 8, 2025
Published online: October 26, 2025
Processing time: 154 Days and 13.8 Hours
BACKGROUND
Myocardial infarction (MI) is a significant global cause of chronic heart failure. In post-ischemic cardiac hypertrophy, multiple molecular targets and signals within the cardiac tissue are evident. Mesenchymal stem cell-derived exosomes (MSC-EXO) and exercise (EXE) showed promise in enhancing post-ischemic cardiac repair.
AIM
To investigate how the exosomes released by stem cells and/or EXE can promote cardiac repair and improve isoproterenol (ISO)-induced post-ischemic hypertrophy.
METHODS
The enrolled animals were divided into 8 control rats and 32 experimental rats. Induction of MI was performed using ISO. Then, the experimental rats were divided into 4 groups: Rats subjected to 4 weeks of swimming EXE, rats treated with exosomes, and the combined treatment. Additionally, functional and interactional exploration of targeted proteins was conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, and STRING database, along with histological examination.
RESULTS
Both MSC-EXO or EXE significantly improved ISO induced elevation of cardiac enzymes, oxidative stress, and inflammatory markers, as well as the degenerative changes of the cardiac muscles, fibrosis, and apoptosis. Meanwhile, the combined treatment of EXE and MSC-EXO resulted in a significant improvement in cardiac function and structure as compared to all groups that synchronized with dual inhibition of extracellular signal-regulated kinase and protein kinase B/mammalian target of rapamycin (P < 0.01) signaling and modulation of matrix metalloproteinase 9 and sarcoplasmic endoplasmic reticulum calcium ATPase type 2a, with significant improved angiogenesis.
CONCLUSION
Functional and structural cardiac improvements are accompanied by reduced inflammation, oxidative stress, and apoptosis. Both MSC-EXO and EXE exert cardio-protection by upregulating sarcoplasmic endoplasmic reticulum calcium ATPase, the critical pump for normal calcium handling.
Core Tip: Myocardial infarction has been extensively validated in rats for reliably inducing post-infarction metabolic and histological changes. Combined therapy may target the extracellular signal-regulated kinase and protein kinase B/mammalian target of rapamycin signaling, both of which are central to the development of hypertrophic remodeling after myocardial infarction, along with the crosstalk between matrix metalloproteinase 9 and sarcoplasmic endoplasmic reticulum calcium ATPase type 2a, which maintains the balance between hypertrophic growth and contractile function. This could offer a new therapeutic regimen for treating early maladaptive left ventricular hypertrophy.
