Mangiferin Attenuates Myocardial Ischemia Reperfusion Injury by Regulating the <scp>GAS6</scp>/Axl Signaling Pathway

Ischemia reperfusion-induced myocardial injury is a prominent pathological feature in patients with coronary artery disease, contributing to significant mortality and morbidity rates. Mangiferin (MGF), the main active ingredient extracted from Anemarrhena asphodeloides Bge, has anti-inflammatory, anti-oxidation, anti-diabetes, and anti-tumor effects. The present study confirmed that the GAS6/Axl pathway was identified as a promising novel target for the treatment of myocardial ischemia reperfusion (IR) injury. However, whether MGF exerts anti-myocardial ischemia reperfusion injury through GAS6/Axl is still unclear. In this study, BALB/c male mice and HL-1 cardiomyocytes were used to construct a model of IR and hypoxia-reoxygenation (HR) (or H₂O₂) injury in vivo and in vitro, respectively. MGF significantly improved cardiac function indicators, myocardial structure, myocardial enzymes, and mitochondrial function, together with reduced oxidative stress and apoptosis in IR-injured mice. In vitro, MGF significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in both HR and H₂O₂-injured HL-1 cells. In particular, the GAS6/Axl signaling pathway plays an important role in this process. Additionally, we also demonstrated that GAS6 gene knockout reversed the protective effect of MGF against HR and H₂O₂-injured cardiomyocytes. The present study confirmed that MGF has protective effects against myocardial IR injury by activating the GAS6/Axl pathway, providing a theoretical basis for MGF as a potential cardioprotective drug in the clinical setting of myocardial IR injury.