4-Hydroxynonenal enhances MMP-9 production in murine macrophages via 5-lipoxygenase-mediated activation of ERK and p38 MAPK |
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Authors: | Seung J Lee Chae E Kim Mi R Yun Kyo W Seo Hye M Park Jung W Yun Hwa K Shin Chi D Kim |
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Affiliation: | a Department of Pharmacology and BK21 Medical Science Education Center, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Korea b MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University, Busan 602-739, Korea c Division of Meridian and Structural Medicine, School of Oriental Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Korea |
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Abstract: | Exaggerated levels of 4-hydroxynonenal (HNE) and 5-lipoxygenase (5-LO) co-exist in macrophages in atherosclerotic lesions, and activated macrophages produce MMP-9 that degrades atherosclerotic plaque constituents. This study investigated the effects of HNE on MMP-9 production, and the potential role for 5-LO derivatives in MMP-9 production in murine macrophages. Stimulation of J774A.1 cells with HNE led to activation of 5-LO, as measured by leukotriene B4 (LTB4) production. This was associated with an increased production of MMP-9, which was blunted by inhibition of 5-LO with MK886, a 5-LO inhibitor or with 5-LO siRNA. A cysteinyl-LT1 (cysLT1) receptor antagonist, REV-5901 as well as a BLT1 receptor antagonist, U-75302, also attenuated MMP-9 production induced by HNE. Furthermore, LTB4 and cysLT (LTC4 and LTD4) enhanced MMP-9 production in macrophages, suggesting a pivotal role for 5-LO in HNE-mediated production of MMP-9. Among the MAPK pathways, LTB4 and cysLT enhanced phosphorylation of ERK and p38 MAPK, but not JNK. Linked to these results, a p38 MAPK inhibitor as well as an ERK inhibitor blunted MMP-9 production induced by LT. Collectively, these data suggest that 5-LO-derived LT mediates HNE-induced MMP-9 production via activation of ERK and p38 MAPK pathways, consequently leading to plaque instability in atherosclerosis. |
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