1. Academic Validation
  2. N-arachidonoylphenolamine alleviates ischaemia/reperfusion-induced cardiomyocyte necroptosis by restoring proteasomal activity

N-arachidonoylphenolamine alleviates ischaemia/reperfusion-induced cardiomyocyte necroptosis by restoring proteasomal activity

  • Eur J Pharmacol. 2023 Dec 13:963:176235. doi: 10.1016/j.ejphar.2023.176235.
Jun-Qin Bai 1 Pang-Bo Li 1 Chun-Min Li 2 Hui-Hua Li 3
Affiliations

Affiliations

  • 1 Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
  • 2 Department of Vascular Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China. Electronic address: lcmbs@126.com.
  • 3 Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China. Electronic address: hhli1935@aliyun.com.
Abstract

Necroptosis and Apoptosis contribute to the pathogenesis of myocardial ischaemia/reperfusion (I/R) injury and subsequent heart failure. N-arachidonoylphenolamine (AM404) is a paracetamol lipid metabolite that has pleiotropic activity to modulate the endocannabinoid system. However, the protective role of AM404 in modulating I/R-mediated myocardial damage and the underlying mechanism remain largely unknown. A murine I/R model was generated by occlusion of the left anterior descending artery. AM404 (20 mg/kg) was injected intraperitoneally into mice at 2 and 24 h before the I/R operation. Our data revealed that AM404 administration to mice greatly ameliorated I/R-triggered impairment of myocardial performance and reduced infarct area, myocyte Apoptosis, oxidative stress and inflammatory response accompanied by the reduction of receptor interacting protein kinase (RIPK)1/3- Mixed Lineage Kinase domain-like (MLKL)-mediated Necroptosis and upregulation of the immunosubunits (β2i and β5i). In contrast, administration of epoxomicin (a Proteasome Inhibitor) dramatically abolished AM404-dependent protection against myocardial I/R damage. Mechanistically, AM404 treatment increases β5i expression, which interacts with Pellino-1 (Peli1), an E3 Ligase, to form a complex with RIPK1/3, thereby promoting their degradation, which leads to inhibition of cardiomyocyte Necroptosis in the I/R heart. In conclusion, these findings demonstrate that AM404 could prevent cardiac I/R damage and may be a promising drug for the treatment of ischaemic heart disease.

Keywords

AM404; Myocardial I/R injury; N-arachidonoylphenolamine; Necroptosis; Oxidative stress; Proteasome.

Figures
Products