Epoxyeicosatrienoic acids (EETs) have anti-inflammatory effects and promote normal endothelial function. The soluble epoxide hydrolase (sEH) metabolizes EETs to their less active diols. We hypothesized that knockdown and inhibition of sEH prevents neointima formation in hyperlipidemic ApoE-/- mice induced by the femoral artery cuff model. Inhibition of sEH by 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) or knockout of the enzyme significantly increased the plasma EET concentration. sEH activity was detectable in femoral arteries. sEH-knockout and inhibition results in a significant reduction of neointima formation (506,3% and 424,7% reduction in intima/media-ratio, p<0.05). The proinflammatory gene expression at the site of cuff placement was significantly reduced in sEH-/--mice. Moreover, an in vivo-BrdU-assay revealed significantly attenuated SMC-proliferation in sEH-/-. Accordingly, SMC-migration activity in cultured cells was attenuated by EETs and this effect was abolished by protein kinase A inhibition. These observations suggest that inhibition of sEH prevents vascular remodelling.

German Research Foundation & Goethe-University