2. Academic Validation
  3. Integrating phosphoproteome and proteome to reveal key processes through which apocynin protects from lethal ventricular arrhythmias-sudden cardiac death in early myocardial ischemia

Integrating phosphoproteome and proteome to reveal key processes through which apocynin protects from lethal ventricular arrhythmias-sudden cardiac death in early myocardial ischemia

  • Toxicol Appl Pharmacol. 2025 Sep:502:117434. doi: 10.1016/j.taap.2025.117434.
Danya Zhou 1,  Huishan Liang 2,  Xiaojun Zhang 3,  Mengxuan Zhang 2,  Wei Zhang 2,  Ye Zhang 2,  Junyao Lv 2,  Xudong Xiao 2,  Guanghui Zhu 2,  Xiaojun Yu 2,  Minchao Lai 4,  Dian Wang 5
Affiliations

Affiliations

  • 1 School of Forensic Medicine, Xinxiang Key Laboratory of Forensic Toxicology, Xinxiang Medical University, Xinxiang, Henan 453003, China; Department of Forensic Medicine, Shantou University Medical College (SUMC), Shantou, Guangdong 515041, China.
  • 2 Department of Forensic Medicine, Shantou University Medical College (SUMC), Shantou, Guangdong 515041, China.
  • 3 Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, Guangdong 515041, China.
  • 4 Department of Neurology, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China. Electronic address: laiminchao0327@outlook.com.
  • 5 Department of Forensic Medicine, Shantou University Medical College (SUMC), Shantou, Guangdong 515041, China. Electronic address: g_dwang@stu.edu.cn.
PMID: 40472975 DOI: 10.1016/j.taap.2025.117434
Abstract

The specific role of NADPH oxidases (NOX)-dependent Reactive Oxygen Species (X-ROS) in the development of lethal ventricular arrhythmias (LVA)-sudden cardiac death (SCD) during the early stage of myocardial ischemia (MI) remains poorly understood. Herein, we investigated the impact of X-ROS on LVA-SCD in early MI. The mouse model of MI-induced LVA-SCD and the apocynin (a NOX inhibitor)-pretreated control groups were established. Survival and the electrophysiological parameters were analyzed, and mitochondrial membrane potential (MMP), superoxide dismutase (SOD) activity, ratio of reduced and oxidized glutathione (GSH/GSSG), and ROS and CA2+ levels were assessed. Additionally, cardiac phosphoproteome and proteome analyses were conducted to explore the phosphorylation-related mechanisms by which apocynin protects against LVA-SCD. Our findings revealed that apocynin reduced the incidence of LVA-SCD in early MI and corrected the ECG alterations associated with LVA. Apocynin also mitigated elevated levels of ROS and CA2+ both in mitochondria and cytosol, and decreased GSH/GSSG ratio, SOD activity, and MMP in SCD. After adjusting for proteome data, 548 proteins showed significant changes in their phosphorylation levels in SCD mice. The up-regulated phosphorylated proteins normalized by apocynin were mainly linked to the tricarboxylic acid cycle (TCA), electron transport chain (ETC) function, and calcium signal pathways. The down-regulated phosphorylated proteins normalized by apocynin were mainly relevant to arrhythmogenic right ventricular cardiomyopathy and AMPK signaling pathway. Collectively, our data suggest that X-ROS promotes LVA-SCD in early MI, with CA2+ imbalance and mitochondrial dysfunction, primarily mediated by phosphorylation changes in mitochondrial proteins, playing a crucial role.

Keywords

Apocynin; Mitochondrial function; Myocardial ischemia; NADPH oxidase -independent ROS (X-ROS); Oxidative stress; Phosphorylation.

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