Soluble epoxide hydrolase inhibitors reduce the development of atherosclerosis in apolipoprotein e-knockout mouse model.
To determine whether sEH inhibitors influence atherosclerotic lesion formation, we used an established murine model of accelerated atherogenesis, ApoE knockout (-/-) mice. The sEH inhibitor, 1-adamantan-3-(5-(2-(2-ethylethoxy)ethoxy)pentyl)urea (AEPU) was delivered in drinking water. All animals were fed an atherogenic diet while simultaneously infused with angiotensin II by osmotic minipump to induce atherosclerosis. In AEPU-treated animals, there was a 53% reduction in atherosclerotic lesions in the descending aortae as compared to control aortae. AEPU and its major metabolites were detected in the plasma of animals which received it. As expected from the inhibition of sEH, a significant increase in linoleic and arachidonic acid epoxides, as well as an increase in individual 11,12-EET/DHET and 14,15-EET/DHET ratios, were observed. The reduction in atherosclerotic lesion area was inversely correlated with 11,12- and 14,15- EET/DHET ratios, suggesting that the reduction corresponds to the inhibition of sEH. Our data suggest that orally-available sEH inhibitors may be useful in the treatment of patients with atherosclerotic cardiovascular disease.
Ulu
Arzu
A
Department of Entomology, University of California Davis, CA, USA.
Davis
Benjamin B
BB
Tsai
Hsing-Ju
HJ
Kim
In-Hae
IH
Morisseau
Christophe
C
Inceoglu
Bora
B
Fiehn
Oliver
O
Hammock
Bruce D
BD
Weiss
Robert H
RH
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D008970:Molecular Weight; D010865:Pilot Projects; D012995:Solubility
D001057:Apolipoproteins E; D000804:Angiotensin II; D004851:Epoxide Hydrolases
Alcohol Clin Exp Res. 2005 Jan;29(1):75-80
15654294
Am J Kidney Dis. 2006 Sep;48(3):341-60
16931208
Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18733-8
17130447
Aliment Pharmacol Ther. 2005 Nov;22 Suppl 2:28-30
16225468
Am J Physiol Renal Physiol. 2004 Apr;286(4):F720-6
14665429
J Biol Chem. 2007 Mar 16;282(11):8343-55
17205981
Cardiovasc Res. 1988 Mar;22(3):213-8
3167945
Mol Cell Biochem. 1994 Oct 26;139(2):141-8
7862104
Toxicol Appl Pharmacol. 2000 Nov 1;168(3):268-79
11042099
J Cardiovasc Pharmacol. 2007 Sep;50(3):225-37
17878749
Mol Biol Cell. 1999 Apr;10(4):961-74
10198050
J Biosci. 2007 Mar;32(2):279-91
17435320
Herz. 2006 Dec;31 Suppl 3:5-24
17577934
Atherosclerosis. 1987 Dec;68(3):231-40
3426656
Nat Med. 1997 May;3(5):562-6
9142128
N Engl J Med. 2004 Sep 23;351(13):1296-305
15385656
J Med Chem. 2007 Oct 18;50(21):5217-26
17894481
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1558-63
12574510
Hypertension. 2005 Oct;46(4):975-81
16157792
Physiol Behav. 1996 Oct;60(4):1053-6
8884932
Sci Am. 2002 May;286(5):46-55
11951331
Bioorg Med Chem Lett. 2006 Oct 1;16(19):5212-6
16870439
Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13646-51
16950874
J Pharmacol Exp Ther. 2006 Sep;318(3):1307-14
16772540
Circulation. 2001 Jan 23;103(3):448-54
11157699
Am J Physiol. 1995 Jan;268(1 Pt 1):L123-8
7840218
J Biol Chem. 2001 May 4;276(18):14867-74
11278979
Science. 1999 Aug 20;285(5431):1276-9
10455056
Anal Biochem. 2005 Aug 1;343(1):66-75
15963942
Ann N Y Acad Sci. 1999 Nov 18;892:108-18
10842656
Clin Chem. 2008 Jan;54(1):24-38
18160725
Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9772-7
15994227
Hypertension. 2005 Apr;45(4):759-65
15699457
Hypertension. 2002 Feb;39(2 Pt 2):690-4
11882632
Biochem Biophys Res Commun. 2006 Mar 3;341(1):254-60
16414022
Am Rev Respir Dis. 1988 Mar;137(3):535-40
3345035