Inhibition of soluble epoxide hydrolase in mice promotes reverse cholesterol transport and regression of atherosclerosis

Li Shen, Hongchun Peng, Ran Peng, Qingsong Fan, Shuiping Zhao, Danyan Xu, Christophe Morisseau, Nipavan Chiamvimonvat, Bruce D. Hammock

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Adipose tissue is the body largest free cholesterol reservoir and abundantly expresses ATP binding cassette transporter A1 (ABCA1), which maintains plasma high-density lipoprotein (HDL) levels. HDLs have a protective role in atherosclerosis by mediating reverse cholesterol transport (RCT). Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has various beneficial effects on cardiovascular disease. The sEH is highly expressed in adipocytes, and it converts epoxyeicosatrienoic acids (EETs) into less bioactive dihydroxyeicosatrienoic acids. We previously showed that increasing EETs levels with a sEH inhibitor (sEHI) (t-AUCB) resulted in elevated ABCA1 expression and promoted ABCA1-mediated cholesterol efflux from 3T3-L1 adipocytes. The present study investigates the impacts of t-AUCB in mice deficient for the low density lipoprotein (LDL) receptor (Ldlr-/- mice) with established atherosclerotic plaques. The sEH inhibitor delivered invivo for 4 weeks decreased the activity of sEH in adipose tissue, enhanced ABCA1 expression and cholesterol efflux from adipose depots, and consequently increased HDL levels. Furthermore, t-AUCB enhanced RCT to the plasma, liver, bile and feces. It also showed the reduction of plasma LDL-C levels. Consistently, t-AUCB-treated mice showed reductions in the size of atherosclerotic plaques. These studies establish that raising adipose ABCA1 expression, cholesterol efflux, and plasma HDL levels with t-AUCB treatment promotes RCT, decreasing LDL-C and atherosclerosis regression, suggesting that sEH inhibition may be a promising strategy to treat atherosclerotic vascular disease.

Original languageEnglish (US)
Pages (from-to)557-565
Number of pages9
JournalAtherosclerosis
Volume239
Issue number2
DOIs
StatePublished - Apr 1 2015

Keywords

  • ABCA1
  • AcLDL
  • ATD
  • ATP binding cassette transporter A1
  • DHETs
  • EETs
  • Epoxyeicosatrienoic acids
  • HDL
  • High density lipoprotein
  • LSC
  • RCT
  • Reverse cholesterol transport
  • SCD
  • SEH
  • SEHI
  • Soluble epoxide hydrolase
  • T-AUCB

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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