Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Oct 26, 2024; 16(10): 873-895
Published online Oct 26, 2024. doi: 10.4252/wjsc.v16.i10.873
Gamma-aminobutyric acid enhances miR-21-5p loading into adipose-derived stem cell extracellular vesicles to alleviate myocardial ischemia-reperfusion injury via TXNIP regulation
Feng-Dan Wang, Yi Ding, Jian-Hong Zhou, En Zhou, Tian-Tian Zhang, Yu-Qi Fan, Qing He, Zong-Qi Zhang, Cheng-Yu Mao, Jun-Feng Zhang, Jing Zhou
Feng-Dan Wang, Jian-Hong Zhou, En Zhou, Tian-Tian Zhang, Yu-Qi Fan, Qing He, Zong-Qi Zhang, Cheng-Yu Mao, Jun-Feng Zhang, Jing Zhou, Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
Yi Ding, Department of Anesthesiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
Co-first authors: Feng-Dan Wang and Yi Ding.
Co-corresponding authors: Jing Zhou and Cheng-Yu Mao.
Author contributions: Wang FD, Ding Y, and Zhou JH contributed equally to this work in performance of the experiments, and review and editing of the manuscript; Zhou E, Zhang TT, Fan YQ, He Q, and Zhang ZQ wrote the paper; Mao CY provided funding for this study; Mao CY, Zhang JF, and Zhou J conceived the study and contributed equally to this work. Wang FD and Ding Y are the co-first authors of this manuscript. Mao CY and Zhou J are the co-corresponding authors of this manuscript. All authors read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 82200270.
Institutional animal care and use committee statement: All animal procedures were approved by the Shanghai Ninth People’s Hospital Institutional Ethics Committee (Approval No. SH9H-2022-A517-SB) and conducted in accordance with the guidelines of the Directive 2010/63/EU of the European Parliament.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Jing Zhou, MM, Doctor, Teacher, Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 280 Mohe Road, Baoshan District, Shanghai 200011, China. zj9hospital@163.com
Received: April 1, 2024
Revised: August 21, 2024
Accepted: September 27, 2024
Published online: October 26, 2024
Processing time: 206 Days and 15.6 Hours
Abstract
BACKGROUND

Myocardial ischemia-reperfusion injury (MIRI) poses a prevalent challenge in current reperfusion therapies, with an absence of efficacious interventions to address the underlying causes.

AIM

To investigate whether the extracellular vesicles (EVs) secreted by adipose mesenchymal stem cells (ADSCs) derived from subcutaneous inguinal adipose tissue (IAT) under γ-aminobutyric acid (GABA) induction (GABA-EVsIAT) demonstrate a more pronounced inhibitory effect on mitochondrial oxidative stress and elucidate the underlying mechanisms.

METHODS

We investigated the potential protective effects of EVs derived from mouse ADSCs pretreated with GABA. We assessed cardiomyocyte injury using terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/propidium iodide assays. The integrity of cardiomyocyte mitochondria morphology was assessed using electron microscopy across various intervention backgrounds. To explore the functional RNA diversity between EVsIAT and GABA-EVsIAT, we employed microRNA (miR) sequencing. Through a dual-luciferase reporter assay, we confirmed the molecular mechanism by which EVs mediate thioredoxin-interacting protein (TXNIP). Western blotting and immunofluorescence were conducted to determine how TXNIP is involved in mediation of oxidative stress and mitochondrial dysfunction.

RESULTS

Our study demonstrates that, under the influence of GABA, ADSCs exhibit an increased capacity to encapsulate a higher abundance of miR-21-5p within EVs. Consequently, this leads to a more pronounced inhibitory effect on mitochondrial oxidative stress compared to EVs from ADSCs without GABA intervention, ultimately resulting in myocardial protection. On a molecular mechanism level, EVs regulate the expression of TXNIP and mitigating excessive oxidative stress in mitochondria during MIRI process to rescue cardiomyocytes.

CONCLUSION

Administration of GABA leads to the specific loading of miR-21-5p into EVs by ADSCs, thereby regulating the expression of TXNIP. The EVs derived from ADSCs treated with GABA effectively ameliorates mitochondrial oxidative stress and mitigates cardiomyocytes damage in the pathological process of MIRI.

Keywords: Extracellular vesicles; Myocardial ischemia-reperfusion injury; Adipose-derived mesenchymal stem cells; Gamma-aminobutyric acid; Thioredoxin-interacting protein

Core Tip: Extracellular vesicles secreted by adipose mesenchymal stem cells derived from subcutaneous inguinal adipose tissue under γ-aminobutyric acid induction demonstrate a pronounced inhibitory effect on mitochondrial oxidative stress and showcases a safeguarding impact on the cardiomyocytes. The protective effects may result from extracellular vesicle microRNA-21-5p targeting thioredoxin (TXNIP)-interacting protein, regulating TXNIP-interacting protein-TXNIP complex formation and subsequent enhancing the antioxidant activity of TXNIP.