Associate editor: R.M. WadsworthFrom endothelium-derived hyperpolarizing factor (EDHF) to angiogenesis: Epoxyeicosatrienoic acids (EETs) and cell signaling
Introduction
Cytochrome P450 (CYP) enzymes are membrane-bound, heme-containing terminal oxidases in a multi-enzyme complex that also includes a FAD/FMN-containing NADPH-cytochrome P450 reductase and cytochrome b5. CYP enzymes oxidize, peroxidise, and/or reduce cholesterol, vitamins, steroids, xenobiotics, and numerous pharmacological substances in an oxygen- and NADPH-dependent manner. Some isoforms are fairly specific in their choice of substrates but many catalyse a large number of chemical reactions and can use an almost unlimited number of biologically occurring and synthetic compounds. Hepatic CYP enzymes are responsible for the metabolism of xenobiotica and many pharmaceuticals, but they also utilize endogenous compounds as substrates, such as cholesterol and fatty acids. Because many CYP enzymes metabolize arachidonic acid, they have been referred to as the third pathway of arachidonic acid metabolism, that is, in addition to cyclooxygenases (COX) and lipoxygenases. Among the CYP enzymes that metabolize arachidonic acid, it is possible to distinguish hydroxylases that form vasoconstrictor hydroxyeicosatetraenoic acids (HETEs) and epoxygenases, which generate vasodilator epoxyeicosatrienoic acids (EETs).
Section snippets
What are epoxyeicosatrienoic acids?
EETs are arachidonic acid epoxides, and in mammals the epoxidation of polyunsaturated fatty acids to cis-epoxides is unique to the CYP enzyme system. Multiple mammalian CYP enzymes are capable of generating EETs including members of the CYP 1A, CYP 2B, CYP 2C, CYP 2D, CYP 2J, and CYP 4A subfamilies (for a review, see Fleming, 2001, Zeldin, 2001), whereas the catalytic efficiency as well as the regio- and enantio-selectivity of EET formation is isoform specific. Of the 5,6-, 8,9-, 11,12-, and
Epoxyeicosatrienoic acid receptors
EETs are now recognized as important modulators of intracellular signaling cascades, but it is unclear how they initiate their effects. Several modes of cell activation by EETs have been proposed. One of them involves the activation of a putative extracellular receptor on guinea pig monocytes (Wong et al., 2000). Competition studies showed a specific high affinity binding of 14,15- and 11,12-EET to a receptor that seems to be protein in nature. Another proposed mechanism involves the
Endothelial cells
The first hint that EETs may affect cell signaling and proliferation was obtained in renal epithelial cells (Chen et al., 1998, Chen et al., 1999) and soon afterwards “authentic EDHF” recovered from the luminal incubate of rhythmically stretched coronary arteries was found to activate a number of kinases, whose function was closely linked with endothelial cell proliferation (Fleming et al., 2001a). The activation of these MAP kinases could be inhibited by the treatment with CYP inhibitors as
Cytochrome P450 epoxygenases/epoxyeicosatrienoic acids and angiogenesis
The first link between EETs and angiogenesis was obtained in co-cultures of astrocytes and endothelial cells. EETs released from astrocytes increased thymidine incorporation into endothelial cells and elicited the formation of capillary like structures (Munzenmaier & Harder, 2000, Zhang & Harder, 2002). Moreover, the overexpression of CYP 2C9 in and/or the application of 11,12- or 14,15-EET to monocultures of endothelial cells was associated with angiogenesis (Medhora et al., 2003, Michaelis et
Summary/outlook
Since the first proposal that CYP-derived metabolites of arachidonic acid may be linked to vascular smooth muscle hyperpolarization and relaxation, it has become clear that the arachidonic acid epoxides (5,6-, 8,9-, 11,12-, and 14,15-EET) are important intracellular signaling molecules that modulate much more than membrane potential. The vasodilator and anti-inflammatory actions of EETs mean that therapies that increase their generation or prevent their degradation may prove beneficial in the
Acknowledgments
Work performed in the author's laboratory was supported by the Deutsche Forschungsgemeinschaft (SFB-TR 23, A6).
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2022, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsCitation Excerpt :The activation of p38 MAPK by PD at 30 min coincides with a reduced production of anti-inflammatory oxylipins such as 5,6-, 8,9- and 11,12-EpETrEs [52]. EpETrEs also have a pro-angiogenic effect [53] and thus lower levels of these EpETrEs after PD treatment may relate to the reduction in cell proliferation that was observed in this study. 13-HDoHE can be generated non-enzymatically from DHA, and is an indicator of oxidative stress [54].