Lipid-metabolizing CYPs in the regulation and dysregulation of metabolism.

The cytochrome P450s (CYPs) represent a highly divergent class of enzymes involved in the oxidation of organic compounds. A subgroup of CYPs metabolize ω3-arachidonic and linoleic acids and ω6-docosahexaenoic and eicosapentaenoic polyunsaturated fatty acids (PUFAs) into a series of related biologically active mediators. Over the past 20 years, increasing evidence has emerged for a role of these PUFA-derived mediators in physiological and pathophysiological processes in the vasculature, during inflammation, and in the regulation of metabolism. With recent technological advances and increased availability of lipid mass spectroscopy, we are now starting to discern the patterns of these CYP-PUFA products in health and disease. These analyses not only are revealing the diverse spectrum of lipid nutrients regulated by CYPs, but also clearly indicate that the balance of these mediators changes with dietary intake of different PUFA classes. These findings suggest that we are only just beginning to understand all of the relevant lipid species produced by CYP pathways. Moreover, we are still a long way from understanding the nature and presence of their receptors, their tissue expression, and the pathophysiological processes they regulate. This review highlights these future issues in the context of lipid-metabolizing CYP enzymes, focusing particularly on the CYP450 family of epoxygenases and the lipid mediators they produce.

Basal and inducible anti-inflammatory epoxygenase activity in endothelial cells.

The roles of CYP lipid-metabolizing pathways in endothelial cells are poorly understood. Human endothelial cells expressed CYP2J2 and soluble epoxide hydrolase (sEH) mRNA and protein. The TLR-4 agonist LPS (1 µg/ml; 24 h) induced CYP2J2 but not sEH mRNA and protein. LC-MS/MS analysis of the stable commonly used human endothelial cell line EA.Hy926 showed active epoxygenase and epoxide hydrolase activity: with arachidonic acid (stable epoxide products 5,6-DHET, and 14,15-DHET), linoleic acid (9,10-EPOME and 12,13-EPOME and their stable epoxide hydrolase products 9,10-DHOME and 12,13-DHOME), docosahexaenoic acid (stable epoxide hydrolase product 19,20-DiHDPA) and eicosapentaenoic acid (stable epoxide hydrolase product 17,18-DHET) being formed. Inhibition of epoxygenases using either SKF525A or MS-PPOH induced TNFα release, but did not affect LPS, IL-1ß, or phorbol-12-myristate-13-acetate (PMA)-induced TNFα release. In contrast, inhibition of soluble epoxide hydrolase by AUDA or TPPU inhibited basal, LPS, IL-1ß and PMA induced TNFα release, and LPS-induced NFκB p65 nuclear translocation. In conclusion, human endothelial cells contain a TLR-4 regulated epoxygenase CYP2J2 and metabolize linoleic acid>eicosapentaenoic acid > arachidonic acid>docosahexaenoic acid to products with anti-inflammatory activity.

Roles of the epoxygenase CYP2J2 in the endothelium.

Cytochrome p450 (CYP)2J2 is an epoxygenase enzyme that metabolises arachidonic acid to epoxyeicosatrienoic acids (EETs). EETs are inactivated by soluble epoxide hydrolase (sEH), which converts them in to their corresponding dihydroxyeicosatrienoic acids (DHETs). CYP2J2 is highly expressed in cardiovascular tissue including the heart and vascular endothelial cells. CYP2J2 and the EETs it produces have been shown to have a diverse range of effects on the vasculature, including the regulation of inflammation, vascular tone, cellular proliferation, angiogenesis, and metabolism. This review will examine these established and emerging roles of CYP2J2 in the biology of vascular endothelial cells.

Anti-inflammatory effects of epoxyeicosatrienoic acids.

Epoxyeicosatrienoic acids (EETs) are generated by the activity of both selective and also more general cytochrome p450 (CYP) enzymes on arachidonic acid and inactivated largely by soluble epoxide hydrolase (sEH), which converts them to their corresponding dihydroxyeicosatrienoic acids (DHETs). EETs have been shown to have a diverse range of effects on the vasculature including relaxation of vascular tone, cellular proliferation, and angiogenesis as well as the migration of smooth muscle cells. This paper will highlight the growing evidence that EETs also mediate a number of anti-inflammatory effects in the cardiovascular system. In particular, numerous studies have demonstrated that potentiation of EET activity using different methods can inhibit inflammatory gene expression and signalling pathways in endothelial cells and monocytes and in models of cardiovascular diseases. The mechanisms by which EETs mediate their effects are largely unknown but may include direct binding to peroxisome proliferator-activated receptors (PPARs), G-protein coupled receptors (GPCRs), or transient receptor potential (TRP) channels, which initiate anti-inflammatory signalling cascades.