Melatonin postconditioning attenuates myocardial ischemia/reperfusion injury by activating YAP to decrease DRP1-mediated mitochondrial fission

  • Eur J Pharmacol. 2026 Apr 15:1021:178827. doi: 10.1016/j.ejphar.2026.178827.
Tian Tian  1 ,  Bin Hu  2 ,  Xin-Tao Li  1 ,  Wen-He Yang  1 ,  Xin-Yue Li  1 ,  Yi Cheng  1 ,  Mu Jin  3 ,  Fu-Shan Xue  4
Affiliations
  • 1. Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 2. Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Department of Anesthesiology, First Affiliated Hospital of USTC, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, China.
  • 3. Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. Electronic address: [email protected].
  • 4. Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Department of Anesthesiology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China. Electronic address: [email protected].
PMID: 41912007 DOI: 10.1016/j.ejphar.2026.178827
Abstract

It remains unclear if Yes-associated protein (YAP) is involved in the protection of melatonin against myocardial ischemia/reperfusion (I/R) injury by regulating mitochondrial fission. In this experiment, an in vivo myocardial I/R injury model was used. Animals were randomly assigned to receive the different interventions: Sham, I/R, 10 mg melatonin, 20 mg melatonin, lysophosphatidic acid (LPA, a YAP agonist), LPA + melatonin, verteporfin (a YAP antagonist) and verteporfin + melatonin. Myocardial infarct size and serum cardiac enzyme levels were measured. Histopathological features, mitochondrial morphology, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, Apoptosis, and dynamic-related protein 1 (DRP1) and YAP expressions of the I/R myocardium were also evaluated. We observed that melatonin postconditioning significantly reduced myocardial infarct size, ameliorated histological changes, and decreased oxidative stress and Apoptosis in the I/R myocardium. These protective effects were associated with enhanced YAP nuclear translocation, increased p-DRP1 Ser637 expression and decreased p-DRP1 Ser616 expression. Activation of YAP with LPA demonstrated a protective effect against myocardial I/R injury, while inhibition of YAP with verteporfin exacerbated myocardial I/R injury and significantly attenuated the protective effect of melatonin postconditioning against myocardial I/R injury. These findings suggest that melatonin postconditioning confers cardioprotection by activating YAP to preserve mitochondrial ultrastructure and attenuate excessive DRP1-mediated fission. These structural changes may contribute to the observed reduction in myocardial injury. While these findings identify YAP activation as a potential therapeutic target, the limited dose range tested precludes determination of an optimal cardioprotective dose. Further studies defining the full dose-response relationship are still necessary to inform potential clinical translation.

Keywords
Dynamic-related protein 1; Ischemia/reperfusion injury; Melatonin; Mitochondrial fission; Yes-associated protein.
Products