Britanin relieves ferroptosis-mediated myocardial ischaemia/reperfusion damage by upregulating GPX4 through activation of AMPK/GSK3β/Nrf2 signalling

• Published in: Pharmaceutical biology Vol. 60; no. 1; pp. 38 - 45
• Main Authors: Lu, Haoyang, Xiao, Hui, Dai, Manyu, Xue, Yangcheng, Zhao, Ren
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01-12-2022; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Adenosine kinase; AMP; AMP-Activated Protein Kinases - metabolism; Animals; Apoptosis; Apoptosis - drug effects; Cell injury; Cell Line; Coronary artery; Creatine; Creatine kinase; Ferroptosis; Ferroptosis - drug effects; Glutathione peroxidase; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - metabolism; Hypoxia; hypoxia-reoxygenation injury; Inflammation; iron; Ischemia; Kinases; L-Lactate dehydrogenase; Lactic acid; Lactones - pharmacology; Male; Myocardial infarction; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - physiopathology; NF-E2-Related Factor 2 - metabolism; Oxidative stress; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Protein kinase; Rats; Rats, Sprague-Dawley; Reperfusion; Sesquiterpenes - pharmacology; Signal transduction; Signal Transduction - drug effects; Up-Regulation - drug effects; Myocardial infarction; apoptosis; iron; hypoxia-reoxygenation injury; oxidative stress
• ISSN: 1388-0209; 1744-5116
• DOI: 10.1080/13880209.2021.2007269

Ferroptosis was described as an important contributor to the myocardial ischaemia/reperfusion (MIR) injury, and britanin (Bri) was reported to exert antitumor and anti-inflammatory activities.
Our study explores the effect and mechanism of Bri on MIR damage.
The rat model of MIR was established by ligation of the left anterior descending coronary artery. Male Sprague-Dawley (SD) rats were divided into three groups: sham group (n = 6), MIR group (n = 6) and MIR + Bri group (n = 6; 50 mg/kg). Rats were intragastrically pre-treated with Bri or normal saline once daily for 3 days. To further verify the role and mechanism of Bri, H9C2 cells were subjected to hypoxia plus reoxygenation (H/R) to induce the in vitro model of MIR.
Compared with MIR rats, Bri significantly decreased infarct area (22.50% vs. 38.67%), myocardial apoptosis (23.00% vs. 41.5%), creatine phosphokinase (0.57 U/mL vs. 0.76 U/mL), and lactate dehydrogenase levels (3.18 U/mL vs. 5.17 U/mL), concomitant with alleviation of ferroptosis. Mechanistically, Bri treatment induced the activation of the adenosine monophosphate activated protein kinase (AMPK)/glycogen synthase kinase 3β (GSK3β)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in vivo. In addition, the AMPK/GSK3β/Nrf2 pathway participated in the regulation of glutathione peroxidase 4 (GPX4) expression, and silencing of Nrf2 attenuated the effect of Bri on H/R-induced cell injury.
Bri protected against ferroptosis-mediated MIR damage by upregulating GPX4 through activation of the AMPK/GSK3β/Nrf2 signalling, suggesting that Bri might become a novel therapeutic agent for MIR.