13-methylpalmatine alleviates myocardial ischemia/reperfusion injury by potentially targeting the C5a-C5aR1 axis to inhibit neutrophil extracellular trap formation

  • Redox Biol. 2025 Aug 5:86:103802. doi: 10.1016/j.redox.2025.103802.
Miao Zhang  1 ,  Shan Gao  2 ,  Nannan Tan  1 ,  Yu Yan  1 ,  Rongxin Zhu  1 ,  Jiajing Liu  1 ,  Qin Mao  1 ,  Keyan Wang  1 ,  Wenhao Zhang  1 ,  Gang Wang  1 ,  Zhuo Wang  1 ,  Tieshan Wang  1 ,  Xueshi Huang  3 ,  Rong Zhang  4 ,  Baofeng Yang  5
Affiliations
  • 1. School of Traditional Chinese Medicine and Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
  • 2. School of Traditional Chinese Medicine and Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381, China.
  • 3. Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
  • 4. School of Traditional Chinese Medicine and Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; School of Chinese Meteria Medica, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address: [email protected].
  • 5. School of Traditional Chinese Medicine and Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China. Electronic address: [email protected].
PMID: 40768896 DOI: 10.1016/j.redox.2025.103802
Abstract

The Complement System activation-induced inflammation is a critical contributor to myocardial ischemia/reperfusion (I/R) injury. However, effective therapeutic targets and pharmacological interventions remain limited. In this study, we identified 13-methylpalmatine (13-Me-PLT), a natural isoquinoline alkaloid isolated from Coptidis chinensis, as a cardio-protective agent that improved cardiac function and reduced inflammation in a rat model of myocardial I/R injury. RNA Sequencing (RNA-seq) analysis revealed significant up-regulation of neutrophil extracellular trap (NET) formation-related signaling pathway and C5ar1 gene in myocardial I/R, both of which were reversed by 13-Me-PLT treatment. Bioinformatics analysis, biophysical assays, and flow cytometry confirmed that 13-Me-PLT effectively inhibited C5a receptor 1 (C5aR1) on neutrophils. However, the role of the C5a-C5aR1 axis in NET formation during myocardial I/R injury has remained unclear. In this study, using a pharmacological inhibitor of C5aR1, we demonstrated that activation of the C5a-C5aR1 axis promoted myocardial I/R injury by inducing NET formation, and that 13-Me-PLT effectively inhibited both processes in a BM213 (C5aR1 agonist)-treated rat model. In vitro, 13-Me-PLT suppressed the expression of NET-associated proteins and alleviated fibrous NET structures in neutrophils, further supporting its cardio-protective effects. In conclusion, our findings revealed that C5a-C5aR1 axis activation exacerbated myocardial I/R injury in a NET-dependent manner. 13-Me-PLT exerted cardio-protective effects by potentially inhibiting C5a-C5aR1 axis-mediated NET formation, highlighting its potential as a therapeutic candidate for myocardial I/R injury.

Keywords
13-Methylpalmatine; C5aR1; Myocardial ischemia/reperfusion; Neutrophil extracellular traps; Transcriptomics.
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