Soluble epoxide hydrolase deficiency attenuates neointima formation in the femoral cuff model of hyperlipidemic mice.
OBJECTIVE
Epoxyeicosatrienoic acids (EETs) have antiinflammatory effects and are required for normal endothelial function. The soluble epoxide hydrolase (sEH) metabolizes EETs to their less active diols. We hypothesized that knockout and inhibition of sEH prevents neointima formation in hyperlipidemic ApoE(-/-) mice.


RESULTS
Inhibition of sEH by 12-(3-adamantan-1-yl-ureido) dodecanoic acid or knockout of the enzyme significantly increased plasma EET levels. sEH activity was detectable in femoral and carotid arteries. sEH knockout or inhibition resulted in a significant reduction of neointima formation in the femoral artery cuff model but not following carotid artery ligation. Although macrophage infiltration occurred abundantly at the site of cuff placement in both sEH(+/+) and sEH(-/-), the expression of proinflammatory genes was significantly reduced in femoral arteries from sEH(-/-) mice. Moreover, an in vivo 5-bromo-2'-deoxyuridine assay revealed that smooth muscle cell proliferation at the site of cuff placement was attenuated in sEH knockout and sEH inhibitor-treated animals.


CONCLUSIONS
These observations suggest that inhibition of sEH prevents vascular remodeling in an inflammatory model but not in a blood flow-dependent model of neointima formation.
Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany.
Marc
M
Revermann
Manuel
M
Schloss
Eduardo
E
Barbosa-Sicard
Anja
A
Mieth
Stefan
S
Liebner
Christophe
C
Morisseau
Gerd
G
Geisslinger
Ralph T
RT
Schermuly
Ingrid
I
Fleming
Bruce D
BD
Hammock
Ralf P
RP
Brandes
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001095:Arachidonic Acids / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002340:Carotid Artery Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D017536:Carotid Artery, Common / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005263:Femoral Artery / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D006949:Hyperlipidemias / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D006965:Hyperplasia; D018836:Inflammation Mediators / Q000378:metabolism; D007850:Lauric Acids / Q000494:pharmacology*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D017539:Tunica Intima / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology
C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D001057:Apolipoproteins E; D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D007850:Lauric Acids; D004851:Epoxide Hydrolases; D000218:Adamantane