Plasma exosomes from patients with acute myocardial infarction alleviate myocardial injury by inhibiting ferroptosis through miR-26b-5p/SLC7A11 axis

Ferroptosis promotes myocardial injury in acute myocardial infarction (AMI). Increasing evidence suggests the crucial role of exosomes in post-AMI pathophysiological regulation. We aimed to investigate the effects and underlying mechanisms of plasma exosomes derived from patients with AMI in inhibiting ferroptosis after AMI.Plasma exosomes were isolated from controls (Con-Exo) and patients with AMI (MI-Exo). These exosomes were incubated with hypoxic cardiomyocytes or intramyocardially injected into the AMI mice. Histopathological changes, cell viability, and cell death were measured to evaluate the myocardial injury. For the ferroptosis evaluation, iron particle deposition, Fe2+, ROS, MDA, GSH, and GPX4 levels were detected. Exosomal miR-26b-5p expression was detected by qRT-PCR, and the targeting relationship between miR-26b-5p and SLC7A11 was confirmed by dual luciferase reporter gene assay. The role of the miR-26b-5p/SLC7A11 axis in the regulation of ferroptosis was validated by rescue experiments in cardiomyocytes.Hypoxia-treatment induced ferroptosis and injury in H9C2 cells and primary cardiomyocytes. MI-Exo performed better than Con-Exo in inhibiting hypoxia-induced ferroptosis. miR-26b-5p expression was downregulated in MI-Exo, and miR-26b-5p overexpression significantly eliminated the inhibitory effect of MI-Exo on ferroptosis. Mechanistically, knockdown of miR-26b-5p upregulated SLC7A11/GSH/GPX4 expressions by directly targeting SLC7A11. Moreover, SLC7A11 silencing also reversed the inhibitory effect of MI-Exo on hypoxia-induced ferroptosis. In vivo, MI-Exo significantly inhibited ferroptosis, reduced myocardial injury, and improved the cardiac function of AMI mice.Our findings revealed a novel mechanism of myocardial protection that downregulation of miR-26b-5p in MI-Exo notably upregulated SLC7A11 expression, thereby inhibiting post-AMI ferroptosis and alleviating myocardial injury.