Naringenin alleviates myocardial ischemia/reperfusion injury by regulating the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) /System xc-/ glutathione peroxidase 4 (GPX4) axis to inhibit ferroptosis

Abstract

Ferroptosis is an important form of myocardial cell death in myocardial ischemia-reperfusion injury (MIRI). Naringenin (NAR), as a flavonoid, has a significant advantage in improving MIRI. But the regulatory effect and mechanism of NAR on ferroptosis in MIRI have not been reported. After the rats were given NAR and induced to form myocardial ischemia-reperfusion (MI/R) injury, Tetrazolium chloride (TTC) staining was used to detect the myocardial infarction area of rats, and Hematoxylin-eosin (H&E) staining was used to detect myocardial injury. The markers of tissue inflammation were detected by ELISA. Serum creatine kinase Serum creatin kinase (CPK), Lactate dehydrogenase (LDH), and lipid peroxide (LPO) and oxidative stress related levels were measured. In addition, iron detection kits were used to detect total iron and Fe 2+ levels in cardiac tissues, and western blot was used to detect the expression of ferroptosis-related proteins and the expression of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4). At the cellular level, H9C2 cardiomyocytes were induced by hypoxia/reoxygenation (H/R), and ferroptosis inducer Erastin was administered to detect cell viability, ferroptosis-related indicators, oxidative stress related indicators, and expressions of Nrf2 and GPX4, to explore the mechanisms involved. NAR alleviated MI/R-induced pathological damage, inflammation and lipid peroxidation in myocardial tissue of rats. NAR adjusted the NRF2 /System xc – /GPX4 axis and improved ferroptosis. At the cellular level, ferroptosis inducer Erastin reversed the protective effect of NAR on H/R-induced H9C2 cardiomyocytes. In conclusion, NAR can alleviate MIRI by regulating the Nrf2/System xc-/GPX4 axis to inhibit ferroptosis.

RETRACTED ARTICLE: Propofol inhibits oxidative stress injury through the glycogen synthase kinase 3 beta/nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway

“…For instance, Nrf2 interacts with Pitx2 to repair heart function by stimulating antioxidant signaling [ 40 ]. However, the dysfunction of Nrf2 induces excessive cardiac oxidative stress, senescence, and cell death [ 41 , 42 ]. Therefore, the activation of Nrf2 signaling may play a beneficial role in the treatment of heart disease.…”

The Polyphenolic Profile and Antioxidant Activity of Five Vegetal Extracts with Hepatoprotective Potential

“…Furthermore, another study highlighted that apigenin activates glutathione peroxidase 4 and alleviates ferroptosis and oxidative stress, which is in concordance with our molecular docking results [79]. Furthermore, it has been shown that naringenin alleviates myocardial ischemia/reperfusion injury by regulating the Nrf2/System xc-/GPx4 axis [80], while rutin induces glutathione peroxidase activity in cadmium-induced oxidative stress [81].…”

Mechanism of Action of Flavonoids of Oxytropis falcata on the Alleviation of Myocardial Ischemia–Reperfusion Injury

“…Luteolin markedly alleviates myocardial injury and cardiac dysfunction by activating the PI3K/Akt pathway and inhibiting the Siti1/NLRP3/NF-κB and ROS-mediated MAPK pathways [ 67 , 68 ]. In addition, naringenin protects against MIRI by regulating the NRF2/System xc-/GPX4 axis and cGMP-PKGIα signaling pathway [ 69 , 70 ]. Other compounds of O. falcata such as 7-hydroxyflavone and isoliquiritigenin also exert anti-inflammatory and antioxidant effects and can attenuate diabetic cardiomyopathy [ 71 , 72 , 73 ].…”