title: Inhibition of soluble epoxide hydrolase alleviated atherosclerosis by reducing monocyte infiltration in Ldlr(-/-) mice.
abstract: Circulating monocytes play pivotal roles in chronic inflammatory diseases. Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, are known to have anti-inflammatory effects and are hydrolyzed by soluble epoxide hydrolase (sEH).
  
  
  
  We aimed to investigate the effect of sEH inhibition in atherogenesis.
  
  
  
  Mice with low-density lipoprotein receptor deficiency (Ldlr(-/-)) with or without sEH inhibitor, and Ldlr/sEH double-knockout (DK) mice were fed a Western-type diet (WTD) for 6weeks to induce arteriosclerosis. Both sEH inhibition and gene depletion decreased the WTD-induced hyperlipidemia, plaque area and macrophage infiltration in mice arterial wall. Ly6C(hi) infiltration of monocytes remained similar in blood, spleen and bone marrow of DK mice, but was decreased in aortic lesions. To further assess the role of sEH or EETs in monocyte/macrophage infiltration in atherogenesis, we transplanted DK bone marrow into Ldlr(-/-) recipients, and then fed mice the WTD. Aortic lesions and Ly6C(hi) monocyte infiltration were reduced in mice with transplanted bone marrow of DK mice without diminishing the cholesterol level. Furthermore, sEH inhibition or gene depletion increased the ratio of EETs/DHETs and diminished the expression of P-selectin glycoprotein ligand 1 (PSGL-1) in mice peripheral-blood mononuclear cells. Monocyte adhesion to P-selectin and to tumor necrosis factor α-activated endothelial cells was also diminished by sEH inhibition.
  
  
  
  sEH inhibition and gene depletion attenuated atherosclerosis in mice by decreasing the infiltration of monocytes into the artery wall. EET and PSGL-1 may play pivotal roles in monocyte/macrophage infiltration and atherogenesis.
authors: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
authors: Dan
authors: D
authors: Li
authors: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
authors: Yajin
authors: Y
authors: Liu
authors: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
authors: Xu
authors: X
authors: Zhang
authors: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
authors: Huizhen
authors: H
authors: Lv
authors: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
authors: Wei
authors: W
authors: Pang
authors: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
authors: Xiaoli
authors: X
authors: Sun
authors: Innovative Medicines & Early Development, AstraZeneca R&D, SE-431 83 Mölndal, Sweden.
authors: Li-Ming
authors: LM
authors: Gan
authors: Department of Entomology and Nematology UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA 95616, USA.
authors: Bruce D
authors: BD
authors: Hammock
authors: Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
authors: Ding
authors: D
authors: Ai
authors: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China; Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China. Electronic address: zhuyi@tmu.edu.cn.
authors: Yi
authors: Y
authors: Zhu
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers; D002448:Cell Adhesion; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D015870:Gene Expression; D006949:Hyperlipidemias; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008264:Macrophages; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D019007:P-Selectin / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency*
chemical_list: D015415:Biomarkers; D008055:Lipids; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011973:Receptors, LDL; D003094:Collagen; D004851:Epoxide Hydrolases
keywords: Atherosclerosis; Epoxyeicosatrienoic acids; Inflammation; Macrophage; Monocyte; P-selectin glycoprotein ligand-1; Soluble epoxide hydrolase