4-Hydroxynonenal enhances CD36 expression on murine macrophages via p38 MAPK-mediated activation of 5-lipoxygenase.
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 microM) 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 B(4) 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 LTB(4) 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.
Yun
Mi R
MR
MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University, Busan, Korea.
Im
Dong S
DS
Lee
Seung J
SJ
Park
Hye M
HM
Bae
Sun S
SS
Lee
Won S
WS
Kim
Chi D
CD
D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation; D005487:Foam Cells / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000447:Aldehydes; D018955:CD36 Antigens; D007093:Imidazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D048051:p38 Mitogen-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal; C093642:SB 203580