EETs alleviate ox-LDL-induced inflammation by inhibiting LOX-1 receptor expression in rat pulmonary arterial endothelial cells

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Publisher: Elsevier B.V.
Document Type: Author abstract
Length: 339 words

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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ejphar.2014.01.045 Byline: Jun-xia Jiang, Shui-juan Zhang, Ya-nan Liu, Xi-xi Lin, Yan-hong Sun, Hui-juan Shen, Xiao-feng Yan, Qiang-min Xie Abstract: 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-[kappa]B (NF-[kappa]B). 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 (1[mu]M). 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 (100[mu]g/mL) were blocked by pharmacological inhibitors of Erk1/2 mitogen-activated protein kinase (MAPK) (U0126), p38 MAPK (SB203580), and NF-[kappa]B (PDTC). In addition, we confirmed that 11,12-EET suppresses phosphorylation of p38, degradation of I[kappa]B[alpha], and activation of NF-[kappa]B (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-[kappa]B 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. Author Affiliation: (a) The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China (b) Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Zhejiang University School of Medicine, Hangzhou 310058, China (c) Laboratory Animal Center of Zhejiang University, Hangzhou 310058, China Article History: Received 5 September 2013; Revised 21 January 2014; Accepted 23 January 2014

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Gale Document Number: GALE|A362314419