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

Abstract

Context 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. Objective Our study explores the effect and mechanism of Bri on MIR damage. Materials and methods 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. Results 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. Discussion and conclusions 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.

Targeting Ferroptosis as a Promising Therapeutic Strategy for Ischemia-Reperfusion Injury

“…Bri has been reported to protect against cerebral I/R injury by regulating the Nrf2 signaling pathway [ 162 ]. In a recent study on MIRI, Bri was shown to exert a protective effect against ferroptosis-mediated myocardial I/R damage by upregulating GPX4 expression through the activation of adenosine monophosphate-activated protein kinase (AMPK)/glycogen synthase kinase 3β (GSK3β)/Nrf2 signaling [ 71 ]. The effects of these agents verified the importance of targeting the Nrf2 pathway to alleviate ferroptosis-mediated I/R injury.…”

The Emerging Role of Ferroptosis in Cardiovascular Diseases

“…Britanin is a drug with anti-inflammatory, antioxidant and anti-tumor effects. Lu et al found in MI/R rat model that Britanin could participate in M/IE protection by up-regulating GPX4 level through AMPK/ GSK3β/Nrf2 signaling axis (Lu et al, 2022). There are multiple regulatory pathways for cardiac ferroptosis, MI/RI may trigger ferroptosis by selectively destroying one or more of these pathways.…”

Ferroptosis and its role in skeletal muscle diseases

“…Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor for cell antioxidants and a crucial ferroptosis regulator ( Dodson et al, 2019 ; Anandhan et al, 2020 ). To stop lipid peroxides-mediated ferroptosis, Nrf2 can directly control the expression level of the GPX4 protein and important genes for GSH synthesis, such as the catalytic and regulatory subunits of glutamate cysteine ligase (GCLC/GCLM), GSS, GR, and XCT ( Chan and Kwong, 2000 ; Madduma Hewage et al, 2017 ; Feng et al, 2021 ; Scibior et al, 2021 ; Lu et al, 2022 ). Meanwhile, with the ability of targeting key genes ( FTH1 , FPN1 ) that regulate iron metabolism, Nrf2 can participate in the process of ferroptosis by affecting intracellular iron levels ( Harada et al, 2011 ; Liu et al, 2020 ).…”