Inhibition of soluble epoxide hydrolase in mice promotes reverse cholesterol transport and regression of atherosclerosis.
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 in vivo 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.
Department of Cardiology, Internal Medicine, Xiangya Second Hospital, Central South University, Changsha, 410011, PR China.
Li
L
Shen
Department of Orthopaedics and Emergency, Changsha Central Hospital, Changsha, 410011, PR China.
Hongchun
H
Peng
Department of Cardiology, Internal Medicine, Xiangya Second Hospital, Central South University, Changsha, 410011, PR China.
Ran
R
Peng
Department of Pathology, Xiangya Second Hospital, Central South University, Changsha, Hunan Province, 410001, PR China.
Qingsong
Q
Fan
Department of Cardiology, Internal Medicine, Xiangya Second Hospital, Central South University, Changsha, 410011, PR China.
Shuiping
S
Zhao
Department of Cardiology, Internal Medicine, Xiangya Second Hospital, Central South University, Changsha, 410011, PR China. Electronic address: xudanyan02@sina.com.
Danyan
D
Xu
Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA, 95616, USA.
Christophe
C
Morisseau
Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, CA, 95616, USA.
Nipavan
N
Chiamvimonvat
Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA, 95616, USA.
Bruce D
BD
Hammock
D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000201:enzymology; D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D015854:Up-Regulation; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D064286:ATP Binding Cassette Transporter 1; D001565:Benzoates; D015415:Biomarkers; D002784:Cholesterol; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases; D011973:Receptors, LDL; D014508:Urea; C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; C577833:Abca1 protein, mouse; C518648:Ephx2 protein, mouse
ATP binding cassette transporter A1; Epoxyeicosatrienoic acids; High density lipoprotein; Reverse cholesterol transport; Soluble epoxide hydrolase