Yun Mi R, Im Dong S, Lee Seung J, Park Hye M, Bae Sun S, Lee Won S, Kim Chi D
MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University, Busan, Korea.
Free Radic Biol Med. 2009 Mar 1;46(5):692-8. doi: 10.1016/j.freeradbiomed.2008.12.013. Epub 2008 Dec 24.
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.
4-羟基壬烯醛（HNE）水平升高与5-脂氧合酶（5-LO）同时存在于动脉粥样硬化病变中，但其在动脉粥样硬化发生过程中的关系尚不清楚。本研究调查了5-LO在HNE诱导的CD36表达和巨噬细胞泡沫细胞形成中的作用，以及HNE与5-LO之间的联系。在J774A.1小鼠巨噬细胞中，HNE（10微摩尔）增强了CD36表达，并伴随着氧化型低密度脂蛋白（oxLDL）摄取增加，而5-LO抑制剂MK886或5-LO小干扰RNA（siRNA）抑制5-LO可使其减弱。在来自5-LO缺陷小鼠的腹腔巨噬细胞中，HNE诱导的CD36表达明显减弱，证实了5-LO在HNE诱导的CD36表达中起关键作用。在一项5-LO活性测定中，用HNE刺激巨噬细胞导致在外源性花生四烯酸存在下白三烯B4生成增加，同时5-LO与核膜的结合增加。在参与5-LO磷酸化的丝裂原活化蛋白激酶（MAPK）途径中，HNE主要激活巨噬细胞中的p38 MAPK，并且p38 MAPK抑制剂SB203580而非细胞外信号调节激酶抑制剂可抑制HNE诱导的白三烯B4生成。总体而言，这些数据表明HNE通过p38 MAPK介导的5-LO激活可能增强CD36表达，从而导致巨噬细胞泡沫细胞的形成。
