4-Hydroxynonenal enhances CD36 expression on murine macrophages via p38 MAPK-mediated activation of 5-lipoxygenase |
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| Authors: | Mi R Yun Dong S Im Seung J Lee Hye M Park Sun S Bae Won S Lee Chi D Kim |
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| Institution: | 1. MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University, Busan 602-739, Korea;2. Department of Pharmacology, College of Medicine, Pusan National University, Busan 602-739, Korea;3. Laboratory of Pharmacology, College of Pharmacy, Pusan National University, Busan 609-735, Korea;1. Department of Environmental Health, School of Public Health and the Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, China;2. Shanghai Key Laboratory of Meteorology and Health, Shanghai, China;3. Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, China;4. Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH, USA;1. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI;2. Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;3. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC;4. Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH;5. Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI;6. Department of Biology, Denison University, Granville, OH;7. Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY;8. Department of Medicine, Medical College of Wisconsin, Milwaukee, WI;1. Unidad de Investigación Médica en Inmunología, UMAE, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, México D.F., Mexico;2. Departamento de Inmunología, ENCB, IPN, México D.F., Mexico |
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| Abstract: | Increased levels of 4-hydroxynonenal (HNE) and 5-lipoxygenase (5-LO) coexist in atherosclerotic lesions but their relationship in atherogenesis is unclear. This study investigated the role of 5-LO in HNE-induced CD36 expression and macrophage foam cell formation, and the link between HNE and 5-LO. In J774A.1 murine macrophages, HNE (10 μM) enhanced CD36 expression in association with an increased uptake of oxLDL, which was blunted by inhibition of 5-LO with MK886, a 5-LO inhibitor, or with 5-LO siRNA. In peritoneal macrophages from 5-LO-deficient mice, HNE-induced CD36 expression was markedly attenuated, confirming a pivotal role of 5-LO in HNE-induced CD36 expression. In an assay for 5-LO activity, stimulation of macrophages with HNE led to increased leukotriene B4 production in the presence of exogenous arachidonic acid in association with an increased association of 5-LO to the nuclear membrane. Among the mitogen-activated protein kinase (MAPK) pathways involved in 5-LO phosphorylation, HNE predominantly activated p38 MAPK in macrophages, and the p38 MAPK inhibitor SB203580, but not an extracellular signal-regulated kinase inhibitor, suppressed HNE-induced LTB4 production. Collectively, these data suggest that p38 MAPK-mediated activation of 5-LO by HNE might enhance CD36 expression, consequently leading to the formation of macrophage foam cells. |
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