Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA.
Sci Signal. 2013 Sep 17;6(293):ra83. doi: 10.1126/scisignal.2004214.
The enzyme 15-lipoxygenase (15-LO) plays a role in atherogenesis (also known as atherosclerosis), but the underlying mechanisms are unclear. We found that 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], the major 15-LO-dependent metabolite of arachidonic acid, stimulated the production of reactive oxygen species (ROS) by monocytes through the xanthine oxidase-mediated activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. ROS production led to the Syk-, Pyk2-, and mitogen-activated protein kinase (MAPK)-dependent production of the proinflammatory cytokine interleukin-17A (IL-17A) in a manner that required the transcription factor CREB (cyclic adenosine monophosphate response element-binding protein). In addition, this pathway was required for the 15(S)-HETE-dependent migration and adhesion of monocytes to endothelial cells. Consistent with these observations, we found that peritoneal macrophages from apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (a mouse model of atherosclerosis) exhibited increased xanthine oxidase and NADPH oxidase activities; ROS production; phosphorylation of Syk, Pyk2, MAPK, and CREB; and IL-17A production compared to those from similarly fed ApoE-/-:12/15-LO-/- mice. These events correlated with increased lipid deposits and numbers of monocytes and macrophages in the aortic arches of ApoE-/- mice, which resulted in atherosclerotic plaque formation. Together, these observations suggest that 15(S)-HETE exacerbates atherogenesis by enhancing CREB-dependent IL-17A production and inflammation.
15-脂氧合酶（15-LO）在动脉粥样硬化（也称为动脉粥样硬化）的发生中起作用，但潜在的机制尚不清楚。我们发现，15(S)-羟基二十碳四烯酸[15(S)-HETE]，花生四烯酸的主要 15-LO 依赖性代谢产物，通过黄嘌呤氧化酶介导的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的激活，刺激单核细胞产生活性氧（ROS）。ROS 的产生导致 Syk、Pyk2 和丝裂原激活蛋白激酶（MAPK）依赖性产生促炎细胞因子白细胞介素-17A（IL-17A），这种方式需要转录因子 CREB（环磷酸腺苷反应元件结合蛋白）。此外，该途径是 15(S)-HETE 依赖性单核细胞迁移和粘附到内皮细胞所必需的。与这些观察结果一致，我们发现，喂食高脂肪饮食（动脉粥样硬化的小鼠模型）的载脂蛋白 E 缺陷（ApoE-/-）小鼠的腹腔巨噬细胞表现出增加的黄嘌呤氧化酶和 NADPH 氧化酶活性；ROS 产生；Syk、Pyk2、MAPK 和 CREB 的磷酸化；和 IL-17A 的产生与来自类似喂养的 ApoE-/-：12/15-LO-/-小鼠相比。这些事件与 ApoE-/-小鼠主动脉弓中脂质沉积和单核细胞和巨噬细胞数量的增加相关，导致动脉粥样硬化斑块形成。总之，这些观察结果表明，15(S)-HETE 通过增强 CREB 依赖性 IL-17A 产生和炎症来加剧动脉粥样硬化的发生。
