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Review
. 2010 Feb;48(2):331-41.
doi: 10.1016/j.yjmcc.2009.10.022. Epub 2009 Nov 3.

Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation

Yangmei Deng  1 , Katherine N Theken, Craig R Lee
Affiliations
Review

Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation

Yangmei Deng et al. J Mol Cell Cardiol. 2010 Feb.

Abstract

The cytochrome P450 (CYP) epoxygenase enzymes CYP2J and CYP2C catalyze the epoxidation of arachidonic acid to epoxyeicosatrienoic acids (EETs), which are rapidly hydrolyzed to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). It is well-established that CYP epoxygenase-derived EETs possess potent vasodilatory effects; however, the cellular effects of EETs and their regulation of various inflammatory processes have become increasingly appreciated in recent years, suggesting that the role of this pathway in the cardiovascular system extends beyond the maintenance of vascular tone. In particular, CYP epoxygenase-derived EETs inhibit endothelial activation and leukocyte adhesion via attenuation of nuclear factor-kappaB activation, inhibit hemostasis, protect against myocardial ischemia-reperfusion injury, and promote endothelial cell survival via modulation of multiple cell signaling pathways. Thus, the CYP epoxygenase pathway is an emerging target for pharmacological manipulation to enhance the cardiovascular protective effects of EETs. This review will focus on the role of the CYP epoxygenase pathway in the regulation of cardiovascular inflammation and (1) describe the functional impact of CYP epoxygenase-derived EET biosynthesis and sEH-mediated EET hydrolysis on key inflammatory process in the cardiovascular system, (2) discuss the potential relevance of this pathway to pathogenesis and treatment of cardiovascular disease, and (3) identify areas for future research.

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Figures

Figure 1
Figure 1. Overview of CYP Epoxygenase Pathway Metabolism
Upon cPLA2 activation, arachidonic acid is released and oxidatively metabolized by cyclooxygenases (COX), lipoxygenases (LOX) and cytochromes P450 (CYP) into biologically active eicosanoids. This review focuses on the CYP epoxygenase pathway. Isoforms from the CYP2J and CYP2C subfamilies synthesize four epoxyeicosatrienoic acid (EET) regioisomers (11,12-EET is shown), which are subsequently incorporated into membrane phospholipids or rapidly hydrolyzed by soluble epoxide hydrolase (sEH) into their corresponding diol dihydroxyeicosatrienoic acid (DHET) metabolites (11,12-DHET is shown). The DHETs generally possess less potent biological activity than EETs.
Figure 2
Figure 2. Overview of the Cardiovascular Protective Effects of CYP Epoxygenase-Derived EETs
A series of recent studies have demonstrated that CYP epoxygenase-derived EETs possess potent cardiovascular protective effects including inhibition of endothelial activation and leukocyte adhesion, inhibition of hemostasis, attenuation of myocardial and endothelial ischemia-reperfusion (I/R) injury, and promotion of endothelial cell survival.
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