title: Induction of oxidative stress by oxidized LDL via meprinα-activated epidermal growth factor receptor in macrophages.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Meprinα promotes OxLDL-induced plaque formation and ROS release by transactivation of the EGFR, followed by activation of the PI3K/Rac1/p38 pathway.
authors.affiliation: Chongqing Key Disciplines, Department of Geriatrics,  Southwest Hospital, Third Military Medical University, Chongqing 400038,  China.
authors.forename: Pan
authors.initials: P
authors.lastname: Gao
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Wang
authors.forename: Dei-Hui
authors.initials: DH
authors.lastname: Qian
authors.forename: Ze-Xue
authors.initials: ZX
authors.lastname: Qin
authors.forename: Jun
authors.initials: J
authors.lastname: Jin
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.forename: Qiao-Ying
authors.initials: QY
authors.lastname: Yuan
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Li
authors.forename: Liang-Yi
authors.initials: LY
authors.lastname: Si
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D008666:Metalloendopeptidases; C053833:meprin A; D020830:rac1 GTP-Binding Protein