Jiang Jun-xia, Zhang Shui-juan, Liu Ya-nan, Lin Xi-xi, Sun Yan-hong, Shen Hui-juan, Yan Xiao-feng, Xie Qiang-min
The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Zhejiang University School of Medicine, Hangzhou 310058, China.
Eur J Pharmacol. 2014 Mar 15;727:43-51. doi: 10.1016/j.ejphar.2014.01.045. Epub 2014 Jan 31.
Oxidized low-density lipoprotein (Ox-LDL) is associated with atherosclerotic events through the modulation of arachidonic acid (AA) metabolism and activation of inflammatory signaling. Cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) mitigate inflammation through nuclear factor-κB (NF-κB). In this study, we explored the effects and mechanisms of exogenous EETs on the ox-LDL-induced inflammation of pulmonary artery endothelial cells (PAECs), which were cultured from rat pulmonary arteries. We determined that pre-treatment with 11,12-EET or 14,15-EET attenuated the ox-LDL-induced expression and release of intercellular adhesion molecule-1 (ICAM-1), E-selectin, and monocyte chemoattractant protein-1 (MCP-1) in a concentration-dependent manner. In addition, the ox-LDL-induced expression of CYP2J4 was upregulated by 11,12-EET and 14,15-EET (1μM). Furthermore, the endothelial receptor of lectin-like oxidized low-density lipoprotein (LOX-1) was downregulated in PAECs treated with EETs. The inflammatory responses evoked by ox-LDL (100μg/mL) were blocked by pharmacological inhibitors of Erk1/2 mitogen-activated protein kinase (MAPK) (U0126), p38 MAPK (SB203580), and NF-κB (PDTC). In addition, we confirmed that 11,12-EET suppresses phosphorylation of p38, degradation of IκBα, and activation of NF-κB (p65), whereas 14,15-EET can significantly suppress the phosphorylation of p38 and Erk1/2. Our results indicate that EETs exert beneficial effects on ox-LDL-induced inflammation primarily through the inhibition of LOX-1 receptor upregulation, MAPK phosphorylation, and NF-κB activation and through the upregulation of CYP2J4 expression. This study helps focus the current understanding of the contribution of EETs to the regulation of the inflammation of pulmonary vascular endothelial cells. Furthermore, the therapeutic potential of targeting the EET pathway in pulmonary vascular disease will be highlighted.
氧化型低密度脂蛋白（Ox-LDL）通过调节花生四烯酸（AA）代谢和激活炎症信号通路与动脉粥样硬化事件相关。细胞色素P450（CYP）环氧合酶衍生的环氧二十碳三烯酸（EETs）通过核因子κB（NF-κB）减轻炎症。在本研究中，我们探讨了外源性EETs对Ox-LDL诱导的大鼠肺动脉培养的肺动脉内皮细胞（PAECs）炎症的影响及其机制。我们确定，用11,12-EET或14,15-EET预处理以浓度依赖的方式减弱了Ox-LDL诱导的细胞间黏附分子-1（ICAM-1）、E-选择素和单核细胞趋化蛋白-1（MCP-1）的表达和释放。此外，11,1
