Induction of oxidative stress by oxidized LDL via meprinα-activated epidermal growth factor receptor in macrophages
| Autor: | Liangyi Si, Qiao-Ying Yuan, Pan Gao, Qiang Xu, Jun Jin, Xue-Jun Li, Xiao-Mei Wang, Ze-Xue Qin, Dei-hui Qian |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
rac1 GTP-Binding Protein
Physiology p38 mitogen-activated protein kinases medicine.medical_treatment Aorta Thoracic p38 Mitogen-Activated Protein Kinases Mice Phosphatidylinositol 3-Kinases Transactivation Apolipoproteins E Growth factor receptor Physiology (medical) medicine Animals Growth factor receptor inhibitor Epidermal growth factor receptor Cells Cultured PI3K/AKT/mTOR pathway Mice Knockout Phosphoinositide 3-kinase biology Macrophages Growth factor Metalloendopeptidases Atherosclerosis ErbB Receptors Lipoproteins LDL Mice Inbred C57BL Disease Models Animal Oxidative Stress biology.protein Cancer research lipids (amino acids peptides and proteins) Reactive Oxygen Species Cardiology and Cardiovascular Medicine Signal Transduction |
| Zdroj: | Cardiovascular Research. 97:533-543 |
| ISSN: | 1755-3245 0008-6363 |
| DOI: | 10.1093/cvr/cvs369 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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