Soluble epoxide hydrolase deficiency attenuates neointima formation in the femoral cuff model of hyperlipidemic mice.

Abstract

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.

METHODS AND 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.

CONCLUSION:

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.

• Authors: Marc Revermann, Manuel Schloss, Eduardo Barbosa-Sicard, Anja Mieth, Stefan Liebner, Christophe Morisseau, Gerd Geisslinger, Ralph T Schermuly, Ingrid Fleming, Bruce D Hammock, Ralf P Brandes
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 5 Pg. 909-14 (May 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20224052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 12-(3-adamantan-1-ylureido)dodecanoic acid
• Apolipoproteins E
• Arachidonic Acids
• Enzyme Inhibitors
• Inflammation Mediators
• Lauric Acids
• Epoxide Hydrolases
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Animals
• Apolipoproteins E (deficiency, genetics)
• Arachidonic Acids (metabolism)
• Atherosclerosis (enzymology, etiology, genetics, pathology, prevention & control)
• Carotid Artery Diseases (enzymology, pathology, prevention & control)
• Carotid Artery, Common (drug effects, enzymology, pathology)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Epoxide Hydrolases (antagonists & inhibitors, deficiency, genetics, metabolism)
• Femoral Artery (drug effects, enzymology, injuries, pathology)
• Hyperlipidemias (complications, enzymology, genetics)
• Hyperplasia
• Inflammation Mediators (metabolism)
• Lauric Acids (pharmacology)
• Macrophages (pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Smooth, Vascular (drug effects, enzymology, injuries, pathology)
• Tunica Intima (drug effects, enzymology, injuries, pathology)