Research Paper Volume 13, Issue 18 pp 22556—22570
MSCs enhances the protective effects of valsartan on attenuating the doxorubicin-induced myocardial injury via AngII/NOX/ROS/MAPK signaling pathway
- 1 Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning, China
- 2 Medical College, Dalian University, Dalian 116622, Liaoning, China
- 3 Department of Cardiology, Jingmen No.1 People’s Hospital, Jingmen 448000, Hubei, China
- 4 Department of Cardiology, People’s Hospital of Jilin City, Jilin 132000, Jilin, China
- 5 Central Laboratory, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning, China
- 6 Life Engineering College, Dalian University, Dalian 116622, Liaoning, China
- 7 Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning, China
- 8 Department of Cardiology, Shanghai Chest Hospital, Changning 200030, Shanghai, China
Received: August 18, 2020 Accepted: August 17, 2021 Published: September 29, 2021
https://doi.org/10.18632/aging.203569How to Cite
Copyright: © 2021 Cheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Objective: To verify if AngII/NOX/ROS/MAPK signaling pathway is involved in Doxorubicin (DOX)-induced myocardial injury and if mesenchymal stem cells (MSCs) could enhance the protective effects of valsartan (Val) on attenuating DOX-induced injury in vitro.
Methods: Reactive oxygen species (ROS) formation and the protein expression of AT1R, NOX2, NOX4, caspase-3, caspase-9 and MAPK signaling were assessed in H9c2 cardiomyocytes exposed to DOX for 24 h in the absence or presence of Val, NADPH oxidase inhibitor DPI or knockdown and overexpression of NADPH oxidase subunit: NOX2 and NOX4, co-culture with MSCs, respectively. Finally, MTT assay was used to determine the cell viability of H9c2 cells, MDA-MB-231 breast cancer cells and A549 pulmonary cancer cells under Val, DOX and Val+ DOX treatments.
Results: DOX increased ROS formation and upregulated proteins expression of AT1R, NOX2, NOX4, caspase-3, caspase-9 and MAPK signaling including p-p38, p-JNK, p-ERK in H9c2 cells. These effects could be attenuated by Val, DPI, NOX2 siRNA and NOX4 siRNA. Meanwhile, overexpression of NOX2 and NOX4 could significantly increase DOX-induced ROS formation and further upregulate apoptotic protein expressions and protein expressions of MAPK signaling. MSCs on top of Val further enhanced the protective effects of Val on reducing the DOX-induced ROS formation and downregulating the expression of apoptotic proteins and MAPK signaling as compared with Val alone in DOX-treated H9c2 cells. Simultaneous Val and DOX treatment did not affect cell viability of DOX-treated MDA-MB-231 breast cancer cells or A549 pulmonary cancer cells but significantly improved cell viability of DOX-treated H9c2 cardiomyocytes.
Conclusions: AT1R/NOX/ROS/MAPK signaling pathway is involved in DOX-induced cardiotoxicity. Val treatment significantly attenuated DOX-induced cardiotoxicity, without affecting the anti-tumor effect of DOX. MSCs enhance the protective effects of Val on reducing the DOX-induced toxicity in H9c2 cells.