Regulation of cardiovascular biology by microsomal epoxide hydrolase

Microsomal epoxide hydrolase/epoxide hydrolase 1 (mEH/EPHX1) works in conjunction with cytochromes P450 to metabolize a variety of compounds, including xenobiotics, pharmaceuticals and endogenous lipids. mEH has been most widely studied for its role in metabolism of xenobiotic and pharmaceutical compounds where it converts hydrophobic and reactive epoxides to hydrophilic diols that are more readily excreted. Inhibition or genetic disruption of mEH can be deleterious in the face of many industrial, environmental or pharmaceutical exposures and EPHX1 polymorphisms are associated with the development of exposure-related cancers. The role of mEH in endogenous epoxy-fatty acid (EpFA) metabolism has been less well studied. In vitro, mEH metabolizes most EpFAs at a far slower rate than soluble epoxide hydrolase (sEH) and has thus been generally considered to exert a minor role in EpFA metabolism in vivo. Indeed, sEH inhibitors or sEH-deficiency increase EpFA levels and are protective in animal models of cardiovascular disease. Recently, however, mEH was found to have a previously unrecognized and substantial role in EpFA metabolism in vivo. While few studies have examined the role of mEH in cardiovascular homeostasis, there is now substantial evidence that mEH can regulate cardiovascular function through regulation of EpFA metabolism. The discovery of a prominent role for mEH in epoxyeicosatrienoic acid (EET) metabolism, in particular, suggests that additional studies on the role of mEH in cardiovascular biology are warranted.