2. Academic Validation
  3. 13-methylpalmatine alleviates myocardial ischemia/reperfusion injury by potentially targeting the C5a-C5aR1 axis to inhibit neutrophil extracellular trap formation

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

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: rongzhang77@163.com.
  • 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: yangbf@ems.hrbmu.edu.cn.
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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