Copyright
©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Mechanism of myocardial damage induced by doxorubicin via calumenin-regulated mitochondrial dynamics and the calcium–Cx43 pathway
He Shi, Song-Ao Yang, Ling-Yu Bai, Jian-Jun Du, Zhe Wu, Zhi-Hui He, Hao Liu, Jia-Yue Cui, Ming Zhao
He Shi, Department of Cardiovascular Medicine, Affiliated Hospital of Beihua University, Jilin Province 132000, China
Song-Ao Yang, Department of Biological Sciences, Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
Ling-Yu Bai, Ming Zhao, Department of Cardiovascular Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
Jian-Jun Du, Department of Cardiovascular Medicine, The First People's Hospital of Horqin District, Tongliao 028000, Inner Mongolia Autonomous Region, China
Zhe Wu, Department of Cardiovascular Medicine, Tongliao Municipal Hospital, Tongliao 028000, Inner Mongolia Autonomous Region, China
Zhi-Hui He, Department of Human Anatomy, Histology and Embryology, Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
Hao Liu, Section of Anatomy, Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
Jia-Yue Cui, College of Basic Medical Sciences, Jilin University, Changchun 130000, Jilin Province, China
Co-first authors: He Shi and Song-Ao Yang.
Co-corresponding authors: Zhi-Hui He and Ming Zhao.
Author contributions: Shi H and Yang SA contributed to conducted the research, writing – original draft; Bai LY contributed to conceptualization, methodology; Du JJ contributed to validation, visualization; Wu Z, Liu H, Cui JY, and He ZH contributed to data curation; Zhao M contributed to designed the research, project administration, writing – review and editing; Shi H, Yang SA, and Bai LY contributed to investigation; Shi H, Yang SA, Bai LY, Wu Z, Liu H, Cui JY, He ZH, and Zhao M contributed to formal analysis. Shi H completed the mapping experiment section and western blot experiment part of this research; Yang SA conceptualized, designed, and supervised the whole process of the project. He searched the literature, revised and submitted the early version of the manuscript. He ZH was instrumental and responsible for data re-analysis and re-interpretation, figure plotting, comprehensive literature search, preparation and submission of the current version of the manuscript. This collaboration between Shi H and Yang SA is crucial for the publication of this manuscript and other manuscripts still in preparation.
Supported by Technology Development of Jilin Province, No: 20190701069GH; and Natural Science Foundation of Inner Mongolia Autonomous Region, No: 2018MS08036, No: 2017MS(LH)0824).
Institutional review board statement: The study was reviewed and approved by the Laboratory of Medical Research and Innovation Center, Affiliated Hospital of Inner Mongolia Minzu University.
Institutional animal care and use committee statement: The requirement for ethics approval was approved by the Research Ethics Committee of Inner Mongolia Minzu University (Approval No. NM-LL-2025-04-23-01).
Conflict-of-interest statement: All authors declare that they have no conflict of interest.
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.
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: Ming Zhao, Department of Cardiovascular Medicine, Affiliated Hospital of Inner Mongolia Minzu University, No. 1742 East Section of Holinhe Street, Tongliao 028000, Inner Mongolia Autonomous Region, China.
langzhe73@163.com
Received: January 11, 2025
Revised: April 1, 2025
Accepted: May 7, 2025
Published online: May 26, 2025
Processing time: 133 Days and 8.2 Hours
BACKGROUND
The clinical application of doxorubicin (DOX) is limited by its potential to cause cardiac cardiotoxicity.
AIM
To investigate the correlation between calumenin (CALU) and mitochondrial kinetic-related proteins in rats with DOX cardiomyopathy.
METHODS
A rat model of DOX-induced cardiomyopathy was used to evaluate the effects of DOX. We observed the effect of DOX on electrical conduction in cardiomyocytes using the electromapping technique. Masson staining was performed to evaluate myocardium fibrosis. Electron microscopy was used to observe the changes in pathological ultrastructure of the myocardium. Western blotting and ELISAs were performed to detect protein levels and intracellular free Ca2+ concentration.
RESULTS
DOX slowed conduction and increased conduction dispersion in cardiomyocytes. The myocardial pathology in rats treated with DOX exhibited a significant deterioration, as demonstrated by an increase in mitochondrial Ca2+ concentration and a decrease in the expression of CALU, optic atrophy-1, and Bcl-2. Additionally, there was an increase in the expression of connexin 43 (Cx43) and the mitochondrial mitotic proteins dynamin-related protein 1, CHOP, Cytochrome C, and Bax in DOX rats. Decreased expression of CALU in cardiomyocytes triggered an increase in cytoplasmic free calcium concentration, which would normally be taken up by mitochondria, but decreased expression of mitochondrial outer membrane fusion proteins triggered a decrease in mitochondrial Ca2+ uptake, and the increase in cytoplasmic free calcium concentration triggered cell apoptosis.
CONCLUSION
Increased cytoplasmic free calcium ion concentration induces calcium overload in ventricular myocytes, leading to decreased Cx43 protein, slowed conduction in myocytes, and increased conduction dispersion, resulting in arrhythmias.
Core Tip: Doxorubicin (DOX) is an antitumor drug, with the main side effect being cardiotoxicity. This study investigated the time course and mechanism of DOX-induced myocardial injury by injecting DOX into rats and conducting cardiac electrophysiological tests and ultrastructural observations of myocardium. The results showed that DOX began to damage myocardial mitochondria as early as the second week after administration. The study clearly demonstrated that DOX causes calcium overload in myocardial cells by reducing calumenin expression, which in turn leads to myocardial cell apoptosis and arrhythmia.
