Soluble epoxide hydrolase: a new target for cardioprotection.
Arachidonic acid is metabolized to a number of bioactive eicosanoid molecules by several enzymes, including enzymes of the COX, lipoxygenase and cytochrome P450 (CYP) monooxygenase pathways. Inhibition of the CYP omega-hydroxylase pathway, stimulation of the CYP-epoxygenase pathway and administration of exogenous epoxyeicosatrienoic acids resulted in cardioprotection in animal models of ischemia; contractile function was improved in mouse hearts subjected to global ischemia/reperfusion, and infarct size was reduced in canine and rat hearts. Cardioprotective effects were also achieved when metabolism of the endogenous epoxyeicosatrienoic acids (EETs) by their major enzymatic hydrolysis pathway was blocked in gene knockout mice (EPHX2-/-) or by inhibitors of soluble epoxide hydrolase (sEH), such as 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). Pretreatment of canine hearts with AUDA dose-dependently reduced infarct size, and AUDA enhanced the infarct-sparing effect of treatment with exogenous EETs. The preliminary results of studies in rodent hearts have also demonstrated that AUDA and AUDA-butyl ester reduce infarct size. These results and others obtained in models of myocardial stunning and hypertrophy suggest that inhibitors of EPHX2 or sEH have therapeutic potential in a broad range of cardiovascular diseases.
Gross
Garrett J
GJ
Medical College of Wisconsin, Department of Pharmacology and Toxicology, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. ggross@mcw.edu
Nithipatikom
Kasem
K