Induction of oxidative stress by oxidized LDL via meprinα-activated epidermal growth factor receptor in macrophages.

Aims The aim of this study was to explore meprinα-mediated transactivation of the epidermal growth factor receptor (EGFR) and reactive oxygen species (ROS) production in macrophages. Methods and results Accelerated atherosclerotic lesions were established by administration of a high-fat diet in apolipoprotein E-deficient (apoE–/–) mice. Lentiviral overexpression of meprinα in the thoracic aortic artery during plaque formation enhanced intra-plaque macrophage induction of ROS as well as formation of atherosclerotic plaques, whereas AG1478 (specific inhibitor of the EGFR) treatment exerted the opposite effect. A meprinα inhibitor abrogated EGFR activation in mice. In cultured J774a.1 macrophages, oxidized low-density lipoprotein (OxLDL) increased ROS formation and EGFR activation through a ligand [heparin-binding epidermal growth factor-like growth factor (HB-EGF)]-dependent pathway. However, a meprinα inhibitor or specific siRNA inhibited ROS production and EGFR activation. Recombinant mouse meprinα enhanced OxLDL-stimulated production of ROS and induced HB-EGF. Inhibition of p38 mitogen-activated protein kinase by SB203580 decreased OxLDL-stimulated production of ROS. Conversely, inhibition of meprinα or PI3K-Rac1 inhibitors also decreased p38 activity in OxLDL-stimulated macrophages. In addition, inhibition of meprinα reversed OxLDL-stimulated activation of PI3K. Conclusion Meprinα promotes OxLDL-induced plaque formation and ROS release by transactivation of the EGFR, followed by activation of the PI3K/Rac1/p38 pathway. [ABSTRACT FROM AUTHOR]