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Inhibition of the soluble epoxide hydrolase (sEH) alters vascular remodeling
Author(s) -
Revermann Marc,
BarbosaSicard Eduardo,
Zwissler Bernhard,
Fleming Ingrid,
Hammock Bruce,
Brandes Ralf Peter
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.479.22
Subject(s) - epoxide hydrolase 2 , neointima , chemistry , inflammation , vascular smooth muscle , pharmacology , medicine , biochemistry , enzyme , smooth muscle , restenosis , stent
Epoxyeicosatrienoic acids (EETs) have potent anti‐inflammatory effects and promote endothelial function. The soluble epoxide hydrolase (sEH) metabolizes EETs to their less active diols (DHETs) and thus inhibition of sEH increases EET concentrations. Since EETs reduce smooth muscle cell (SMC) migration, proliferation and monocyte adhesion to the vascular wall in vitro , we hypothesized that inhibition of sEH using 12‐(3‐adamantan‐1‐yl‐ureido) dodecanoic acid (AUDA) prevents vascular remodeling in hyperlipidemic ApoE−/− mice. Remodeling was studied using models with different inflammatory and SMC‐stimulating properties. AUDA increased the ratio of EETs to DHETs in all models. The effect of AUDA in the femoral artery cuff model was a significant reduction of inflammation‐accompanied neointima within 2 weeks (43% reduction in intima/media ratio ‐ IMR, p<0,05). Carotid artery ligation induced a mainly SMC‐formed neointima within 4 weeks and this effect was significantly attenuated by AUDA (64% reduction in IMR, p<0,05). Angiotensin II infusion causes severe aortic inflammation aneurysm formation. In this model AUDA reduced thoracic aorta remodeling (26% less diameter, p<0.05). Taken together, these data demonstrate that sEH‐inhibition attenuates vascular remodeling ‐ probably via alteration of SMC‐activity and augmentation of anti‐inflammatory, the vascular wall protecting EET‐effects. Funding: German Research Foundation & J.W. Goethe‐University