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CARDIOVASCULAR

Activation of Peroxisome Proliferator-Activated Receptor by Substituted Urea-Derived Soluble Epoxide Hydrolase Inhibitors

Departments of Biochemistry (X.F., S.H., G.D.S., J.Y., A.A.S.), Internal Medicine (N.L.W., A.A.S.), and Radiation Oncology (N.L.W.), Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Entomology and Cancer Research Center (T.W., B.D.H.), University of California, Davis, California; Veterans Administration Medical Center (N.L.W.), Iowa City, Iowa; and Department of Cell Biology and Neuroscience (Y.L., J.Y.-J.S.), University of California, Riverside, California

Soluble epoxide hydrolase (sEH) plays a major role in regulating vascular epoxyeicosatrienoic acid metabolism and function, and substituted urea derivatives that inhibit sEH activity reduce blood pressure in hypertensive rats. We found that substituted urea derivatives containing a dodecanoic acid group, besides effectively inhibiting sEH, increased peroxisome proliferator-activated receptor (PPAR) activity. In PPAR transfected COS-7 cells, treatment with 10 µM N-cyclohexyl-N'-dodecanoic acid urea (CUDA) or N-adamantanyl-N'-dodecanoic acid urea (AUDA) produced 6- and 3-fold increases, respectively, in PPAR activation. Neither CUDA nor AUDA activated PPAR or PPAR directly, indicating selectivity for PPAR. CUDA did not alter PPAR protein expression, and it competitively inhibited the binding of Wy-14643 (pirinixic acid) to the ligand binding domain of PPAR, suggesting that it functions as a PPAR ligand. CUDA and AUDA were metabolized to chain-shortened -oxidation products, a process that reduced their potency as sEH inhibitors and their ability to bind and activate PPAR. N,N'-Dicylclohexylurea and N-cyclohexyl-N'-dodecylurea, sEH inhibitors that do not contain a carboxylic acid group, did not activate PPAR. In HepG2 cells, CUDA increased the expression of the PPAR-responsive gene carnitine palmitoyltransferase 1A. We conclude that CUDA and AUDA, by virtue of their carboxylic acid substitution, activate PPAR in addition to potently inhibiting sEH. Further development of these compounds could lead to a class of agents with hypotensive and lipid-lowering properties that may be valuable for the prevention and treatment of cardiovascular disease.

Address correspondence to: Dr. Xiang Fang, Department of Biochemistry, 4-403 BSB, University of Iowa Carver College of Medicine, Iowa City, IA 52242. E-mail: xiang-fang{at}uiowa.edu

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