Inhibition of soluble epoxide hydrolase alleviated atherosclerosis by reducing monocyte infiltration in Ldlr−/− mice

Dan Li, Yajin Liu, Xu Zhang, Huizhen Lv, Wei Pang, Xiaoli Sun, Li Ming Gan, Bruce D. Hammock, Ding Ai, Yi Zhu

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Rationale 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). Objective We aimed to investigate the effect of sEH inhibition in atherogenesis. Methods and results 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 6 weeks to induce arteriosclerosis. Both sEH inhibition and gene depletion decreased the WTD–induced hyperlipidemia, plaque area and macrophage infiltration in mice arterial wall. Ly6Chi 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 Ly6Chi 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. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)128-137
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume98
DOIs
StatePublished - Sep 1 2016

Keywords

  • Atherosclerosis
  • Epoxyeicosatrienoic acids
  • Inflammation
  • Macrophage
  • Monocyte
  • P-selectin glycoprotein ligand-1
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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