Vascular protective effects of cytochrome p450 epoxygenase-derived eicosanoids

Abstract

Cytochrome P450 epoxygenases metabolize arachidonic acid to biologically active eicosanoids. Primary epoxidation products are four regioisomers of cis-epoxyeicosatrienoic acid (EET), 5,6-, 8,9-, 11,12-, and 14,15-EET. One of the predominant epoxygenase isoforms involved in EET formation belongs to the CYP2 gene family. In humans, the P450 epoxygenase, CYP2J2, is expressed in the cardiovascular system, namely the endothelium, vascular smooth muscle, and cardiomyocyte. CYP2J2 possesses vascular protective effects, which include but are not limited to, protection against ischemia-reperfusion injury, suppression of reactive oxygen species following hypoxia-reoxygenation, inhibition of the pro-inflammatory transcription factor, nuclear factor-kappaB (NF-kappaB), attenuation of vascular smooth muscle migration, and enhancement of a fibrinolytic pathway. Although regioisomers of EET elicit these effects to varying degrees, 11,12-EET appears to be the most potent with respect to anti-inflammatory, anti-migratory, and pro-fibrinolytic effects. Thus, CYP2J2 and its derived arachidonic acid metabolites may play important roles in regulating vascular function under normal and pathophysiological conditions.