NOX2 inhibition stabilizes vulnerable plaques by enhancing macrophage efferocytosis via MertK/PI3K/AKT pathway
NADPH oxidases 2 (NOX2) may be the primary supply of ROS in macrophages, which plays a vital role within the formation of coronary artery disease. However, results of NOX2 inhibition on established vulnerable plaques and also the potential role involved remain unclear. The objective of this research would be to investigate latent mechanism of NOX2-triggered vulnerable plaque development. We generated a vulnerable carotid plaque model caused by carotid branch ligation and kidney artery constriction, coupled with a higher-fat diet in ApoE-/- rodents. NOX2 specific inhibitor, GSK2795039 (10 mg/kg/day by intragastric administration for 8 days) considerably avoided vulnerable plaque, evaluated by micro-ultrasound imaging parameters. An account of less intraplaque hemorrhage recognition, elevated bovine collagen-fat ratio, ” floating ” fibrous cap thickness and fewer necrotic core formation were also present in GSK2795039 treated group. Mechanistically, reduced 4-HNE, in situ lesional apoptosis that has been enhanced efferocytosis were involved with rodents given NOX2 inhibitor. Further analysis in mouse macrophages confirmed the function of NOX2 inhibition in enhancing macrophage efferocytosis by controlling the MertK/PI3K/AKT path. In conclusion, our data defined formerly couple of recognized roles of NOX2 in vulnerable plaque pathogenesis as well as an undescribed NOX2-ROS-MerTK axis functions involved with controlling macrophage efferocytosis within the formation of rupture-prone vulnerable plaques.