mROS‑calcium feedback loop promotes lethal ventricular arrhythmias and sudden cardiac death in early myocardial ischemia

Zhou,Danya; Zhou,Danya; Zhou,Danya; Zhou,Danya; Zhang,Ye; Zhang,Ye; Zhang,Ye; Zhang,Ye; Zhu,Mengting; Zhu,Mengting; Zhu,Mengting; Zhu,Mengting; Zhang,Xiaojun; Zhang,Xiaojun; Zhang,Xiaojun; Zhang,Xiaojun; Zhang,Xiaojuan; Zhang,Xiaojuan; Zhang,Xiaojuan; Zhang,Xiaojuan; Lv,Junyao; Lv,Junyao; Lv,Junyao; Lv,Junyao; Tang,Wanting; Tang,Wanting; Tang,Wanting; Tang,Wanting; Weng,Qi; Weng,Qi; Weng,Qi; Weng,Qi; Lin,Yang; Lin,Yang; Lin,Yang; Lin,Yang; Tong,Lejun; Tong,Lejun; Tong,Lejun; Tong,Lejun; Zhong,Zhiwei; Zhong,Zhiwei; Zhong,Zhiwei; Zhong,Zhiwei; Zhang,Yanmei; Zhang,Yanmei; Zhang,Yanmei; Zhang,Yanmei; Zhang,Mengxuan; Zhang,Mengxuan; Zhang,Mengxuan; Zhang,Mengxuan; Lai,Minchao; Lai,Minchao; Lai,Minchao; Lai,Minchao; Wang,Dian; Wang,Dian; Wang,Dian; Wang,Dian

doi:10.3892/ijmm.2023.5329

mROS‑calcium feedback loop promotes lethal ventricular arrhythmias and sudden cardiac death in early myocardial ischemia

Authors:
- Danya Zhou
- Ye Zhang
- Mengting Zhu
- Xiaojun Zhang
- Xiaojuan Zhang
- Junyao Lv
- Wanting Tang
- Qi Weng
- Yang Lin
- Lejun Tong
- Zhiwei Zhong
- Yanmei Zhang
- Mengxuan Zhang
- Minchao Lai
- Dian Wang
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Affiliations: Department of Forensic Medicine, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China, Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, Guangdong 515041, P.R. China, Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China, Department of Neurology, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
Published online on: November 20, 2023 https://doi.org/10.3892/ijmm.2023.5329
Article Number: 5
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lethal ventricular arrhythmia‑sudden cardiac death (LVA‑SCD) occurs frequently during the early stage of myocardial ischemia (MI). However, the mechanism underlying higher LVA‑SCD incidence is still poorly understood. The present study aimed to explore the role of mitochondrial reactive oxygen species (mROS) and Ca²⁺ crosstalk in promoting LVA‑SCD in early MI. RyR2 S2814A mice and their wild‑type littermates were used. MitoTEMPO was applied to scavenge mitochondrial ROS (mROS). Mice were subjected to severe MI and the occurrence of LVA‑SCD was evaluated. Levels of mitochondrial ROS and calcium (mitoCa²⁺), cytosolic ROS (cytoROS), and calcium (cytoCa²⁺), RyR2 Ser‑2814 phosphorylation, CaMKII Met‑282 oxidation, mitochondrial membrane potential (MMP), and glutathione/oxidized glutathione (GSH/GSSG) ratio in the myocardia were detected. Dynamic changes in mROS after hypoxia were investigated using H9c2 cells. Moreover, the myocardial phosphoproteome was analyzed to explore the related mechanisms facilitating mROS‑Ca²⁺ crosstalk and LVA‑SCD. There was a high incidence (~33.9%) of LVA‑SCD in early MI. Mice who underwent SCD displayed notably elevated levels of myocardial ROS and mROS, and the latter was validated in H9c2 cells. These mice also demonstrated overloads of cytoplasmic and mitochondrial Ca²⁺, decreased MMP and reduced GSH/GSSG ratio, upregulated RyR2‑S2814 phosphorylation and CaMKII‑M282 oxidation and transient hyperphosphorylation of mitochondrial proteomes in the myocardium. mROS‑specific scavenging by a mitochondria‑targeted antioxidant agent (MitoTEMPO) corrected these SCD‑induced alterations. S2814A mice with a genetically inactivated CaMKII phosphorylation site in RyR2 exhibited decreased overloads in cytoplasmic and mitochondrial Ca²⁺ and demonstrated similar effects as MitoTEMPO to correct SCD‑induced changes and prevent SCD post‑MI. The data confirmed crosstalk between mROS and Ca2+ in promoting LVA‑SCD. Therefore, we provided evidence that there is a higher incidence of LVA‑SCD in early MI, which may be attributed to a positive feedback loop between mROS and Ca²⁺ imbalance.

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