Attenuation of vascular smooth muscle cell proliferation by 1-cyclohexyl-3-dodecyl urea is independent of soluble epoxide hydrolase inhibition.
Epoxyeicosatrienoic acid(s) (EET) have variable hemodynamic, anti-inflammatory, and growth regulatory effects, and inhibitors of their regulatory enzyme, soluble epoxide hydrolase (sEH), can mimic these effects. For this reason, sEH inhibitors are being studied as potential pharmaceuticals for the treatment of hypertension, atherosclerosis, and inflammatory diseases. We now show that a highly selective urea-based sEH inhibitor 1-cyclohexyl-3-dodecyl urea (CDU) attenuates human aortic vascular smooth muscle (HVSM) cell proliferation independently of any effect on sEH. CDU also inhibits endothelial cells when stimulated with basic fibroblast growth factor or serum. In addition, we demonstrate that EET, as well as several newer generation sEH inhibitors and a urea-based weak sEH inhibitor, do not affect proliferation in HVSM cells. Structure-activity relationships demonstrate that the addition of an acid group to the dodecyl carbon chain, changing the cyclohexyl group to an adamantyl group, and shortening the carbon chain to two carbons all abolish the antiproliferative effect. Our finding that a highly selective urea-based inhibitor of sEH can alter biology independently of its putative target enzyme suggests that there may be other useful properties of this class of compounds unrelated to their influence on epoxyeicosanoids. In addition, our results show that caution should be used when attempting to infer conclusions of EET biology based solely on the effects these inhibitors in tissue culture models, especially when used at micromolar concentrations.
Davis
Benjamin B
BB
Division of Nephrology, Department of Internal Medicine, University of California, Davis, 95616, USA.
Morisseau
Christophe
C
Newman
John W
JW
Pedersen
Theresa L
TL
Hammock
Bruce D
BD
Weiss
Robert H
RH
D001011:Aorta / Q000166:cytology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004537:Eicosanoic Acids / Q000037:antagonists & inhibitors; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology; D012995:Solubility; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C450146:1-cyclohexyl-3-dodecylurea; D004537:Eicosanoic Acids; D014508:Urea; D004851:Epoxide Hydrolases