PMID- 24486707 OWN - NLM STAT- MEDLINE DCOM- 20150129 LR - 20220331 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 727 DP - 2014 Mar 15 TI - EETs alleviate ox-LDL-induced inflammation by inhibiting LOX-1 receptor expression in rat pulmonary arterial endothelial cells. PG - 43-51 LID - S0014-2999(14)00075-2 [pii] LID - 10.1016/j.ejphar.2014.01.045 [doi] AB - 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-kappaB (NF-kappaB). 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 (1muM). 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 (100mug/mL) were blocked by pharmacological inhibitors of Erk1/2 mitogen-activated protein kinase (MAPK) (U0126), p38 MAPK (SB203580), and NF-kappaB (PDTC). In addition, we confirmed that 11,12-EET suppresses phosphorylation of p38, degradation of IkappaBalpha, and activation of NF-kappaB (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-kappaB 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. CI - Copyright (c) 2014 Elsevier B.V. All rights reserved. FAU - Jiang, Jun-xia AU - Jiang JX AD - The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. FAU - Zhang, Shui-juan AU - Zhang SJ AD - Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Zhejiang University School of Medicine, Hangzhou 310058, China. FAU - Liu, Ya-nan AU - Liu YN AD - The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. FAU - Lin, Xi-xi AU - Lin XX AD - Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Zhejiang University School of Medicine, Hangzhou 310058, China. FAU - Sun, Yan-hong AU - Sun YH AD - Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Zhejiang University School of Medicine, Hangzhou 310058, China. FAU - Shen, Hui-juan AU - Shen HJ AD - The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. FAU - Yan, Xiao-feng AU - Yan XF AD - The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: yanxiaofeng0804@sina.com. FAU - Xie, Qiang-min AU - Xie QM AD - Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Zhejiang University School of Medicine, Hangzhou 310058, China; Laboratory Animal Center of Zhejiang University, Hangzhou 310058, China. Electronic address: xieqm@zju.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140131 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Inflammation Mediators) RN - 0 (Lipoproteins, LDL) RN - 0 (NF-kappa B) RN - 0 (OLR1 protein, rat) RN - 0 (RNA, Messenger) RN - 0 (Scavenger Receptors, Class E) RN - 0 (oxidized low density lipoprotein) RN - 5DOQ38R4UW (11,12-epoxy-5,8,14-eicosatrienoic acid) RN - 81276-03-1 (14,15-epoxy-5,8,11-eicosatrienoic acid) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.14.14.1 (Cyp2j4 protein, rat) RN - EC 1.14.14.1 (Cytochrome P450 Family 2) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - FC398RK06S (8,11,14-Eicosatrienoic Acid) SB - IM MH - 8,11,14-Eicosatrienoic Acid/*analogs & derivatives/pharmacology MH - Animals MH - Anti-Inflammatory Agents/*pharmacology MH - Cells, Cultured MH - Cytochrome P-450 Enzyme System/metabolism MH - Cytochrome P450 Family 2 MH - Dose-Response Relationship, Drug MH - Endothelial Cells/*drug effects/metabolism MH - Enzyme Activation MH - Inflammation/genetics/metabolism/*prevention & control MH - Inflammation Mediators/*metabolism MH - Lipoproteins, LDL/*metabolism MH - Male MH - Mitogen-Activated Protein Kinases/metabolism MH - NF-kappa B/metabolism MH - Phosphorylation MH - Pulmonary Artery/*drug effects/metabolism MH - RNA, Messenger/metabolism MH - Rats, Sprague-Dawley MH - Scavenger Receptors, Class E/*drug effects/metabolism MH - Signal Transduction/drug effects OTO - NOTNLM OT - CYP2J4 OT - Inflammation OT - MAPK OT - NF-kappaB OT - Ox-LDL OT - Rat pulmonary arterial endothelial cells EDAT- 2014/02/04 06:00 MHDA- 2015/01/30 06:00 CRDT- 2014/02/04 06:00 PHST- 2013/09/05 00:00 [received] PHST- 2014/01/21 00:00 [revised] PHST- 2014/01/23 00:00 [accepted] PHST- 2014/02/04 06:00 [entrez] PHST- 2014/02/04 06:00 [pubmed] PHST- 2015/01/30 06:00 [medline] AID - S0014-2999(14)00075-2 [pii] AID - 10.1016/j.ejphar.2014.01.045 [doi] PST - ppublish SO - Eur J Pharmacol. 2014 Mar 15;727:43-51. doi: 10.1016/j.ejphar.2014.01.045. Epub 2014 Jan 31.