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Symposium Reports |
1 Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London, Queen Mary University London, Charterhouse Square, London EC1M 6BQ, UK
Abstract
Epoxygenases, particularly of the CYP2C and CYP2J families, are important lipid-metabolizing enzymes. Epoxygenases are found throughout the cardiovascular system where their lipid products, particularly the epoxyeicosatrienoic acids (EETs), which are arachidonic acid metabolites, have the potential to regulate vascular tone, cellular proliferation, migration, inflammation and cardiac function. The receptors for EETs are, however, poorly understood. The peroxisome proliferator-activated receptors (PPARs) are a family of three (
, β/
and 
) nuclear receptors that are activated by lipid metabolites. Activation of PPAR and PPAR, similar to the longer term effects of EETs, causes the inhibition of vascular cell proliferation, migration and inflammation. Interestingly, EETs and their metabolites have recently been found to active both PPAR and PPAR. The epoxygenase–EET–PPAR pathway may therefore represent a novel endogenous protective pathway by which short-lived lipid mediators control vascular cell activation.
(Received 25 June 2007;
accepted after revision 5 September 2007; first published online 14 September 2007)
Corresponding author D. Bishop-Bailey: Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London, Queen Mary University London, Charterhouse Square, London EC1M 6BQ, UK. Email: d.bishop-bailey{at}qmul.ac.uk
Epoxygenases
The epoxygenase enzymes are a group of microsomal cytochrome P450s (CYP) which catalyse the conversion of arachidonic acid (AA) to produce four regio-isomeric epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12- and 14,15-EETs. The epoxygenase pathway of arachidonic acid metabolism is by no means secondary to the widely characterized cyclo-oxygenase (COX) and lipoxygenase pathways. Epoxygenase enzymes (primarily of the CYP2C and CYP2J families) appear to be the prime route of arachidonic acid metabolism in small blood vessels (Harder et al. 1994; Imig et al. 1996), the kidney (Omata et al. 1992; Ito et al. 1998), the heart (Wu et al. 1996, 1997; Chen et al. 1999; Scarborough et al. 1999) and leucocytes (Rosolowsky et al. 1996).
Each epoxygenase generates a select profile of AA metabolites, which is not reflected by their nomenclature. For example, CYP2C8 and CYP2C9 are 80% identical, are both expressed in the human liver and are both classed as epoxygenases; however, CYP2C8 produces 11,12-EET and 14,15-EET in equal amounts, whereas CYP2C9 produces 14,15-EET < 11,12-EET < 8,9-EET (Daikh et al. 1994). In addition to this regio-selectivity in the production of EETs, in some cases, epoxygenases can produce selective EET enantiomers. The CYP2C8 products, mostly 11,12-EET and 14,15-EET, are formed as 11(R),12(S)-EET and 14(R),15(S)-EET enantiomers (Daikh et al. 1994; Zeldin et al. 1996), whereas the EETs that CYP2C9 produces are formed as 11(S),12(R)-EET and 14(R),15(S)-EET (Daikh et al. 1994).
Once produced, epoxygenase metabolites are tightly regulated. Epoxyeicosatrienoic acids are usually heavily (90%) esterified to phospholipids, leaving approximately 1 nM free (Karara et al. 1992). Free EETs are readily incorporated into phospholipids (Fang et al. 1995), but at a lower rate than their precursor, arachidonic acid (Bernstrom et al. 1992). Analysis of the phospholipid pools show that EETs are commonly esterified at the sn-2 position (Karara et al. 1991), where they are stored until stimulated to be released into the cell for further effects and metabolism.
Epoxyeicosatrienoic acid metabolism
In most cells and tissues, the EETs are unstable and are rapidly metabolized. A major pathway of EET metabolism is that catalysed by epoxide hydrolases (Zeldin et al. 1993), mainly through the soluble epoxide hydrolase (Zeldin et al. 1993, 1995a) to produce dihydroxyeicosatrienoic acids (Zeldin et al. 1995c). Moreover, the fact that dihydroxyeicosatrienoic acids are constituents of liver, lung and urine confirms that EET hydration is highly likely to occur in vivo (Zeldin et al. 1995b, 1996). The conversion of free EETs to dihydroxyeicosatrienoic acids in most cells occurs rapidly (Fang et al. 1995). Dihydroxyeicosatrienoic acids have a lower binding affinity to phospholipids than EETs (Weintraub et al. 1999), which may explain why, compared with EETs, dihydroxyeicosatrienoic acids tend to be detectable in the cytoplasm, metabolized further or released from cells (Weintraub et al. 1999). In addition to soluble epoxide hydrolase, EETs are also substrates for the COX enzymes (Carroll & McGiff, 2000) and for glutathione S-transferase, making glutathione conjugates (Spearman et al. 1985), as well as being metabolized by additional CYPs (Capdevila et al. 1988; Ortiz De Montellano, 1995).
Roles of epoxygenases and their products in the control of vascular tone
When analysing the effects of epoxygenases and their products in the vasculature, it is impossible not to include their candidacy as the acutely released endothelium-derived hyperpolarizing factors (EDHF). Local vascular tone is determined by extrinsic and intrinsic mechanisms, such as autonomic nerve activity, circulating vasoactive compounds, tissue metabolites, the myogenic response and endothelium-derived autacoids (Fisslthaler et al. 2003). The best characterized autacoids are the potent vasodilators nitric oxide (NO) and prostaglandin I2 (PGI2). However, an endothelium-derived vasodilating and hyperpolarizing factor that is distinct from NO or prostacyclin has been established. In some studies, NO/PGI2-independent vasodilatation is sensitive to inhibitors of CYPs (Singer et al. 1984; Rubanyi & Vanhoutte, 1987; Pinto et al. 1987; Fulton et al. 1995; Campbell et al. 1996) and, considering that endothelial cells contain epoxygenases (Johnson et al. 1985; Abraham et al. 1985), it was proposed that EETs may be the source of these unknown vasodilator(s). Preconstricted bovine coronary arteries relax upon addition of all isoforms of EETs (Campbell et al. 1996). Moreover, antisense inhibition of CYP2C8/9 in arteries from hamster gracilis muscle decreases EDHF responses by 70% (Bolz et al. 2000). Similarly, in porcine coronary arteries, the CYP2C9 inhibitor sulphaphenazole abolished EDHF (Fisslthaler et al. 2000), while overexpression of CYP2C enhanced production of 11,12-EET and EDHF responses (Fisslthaler et al. 1999).
There have been relatively few studies conducted on EDHF in humans. The addition of sulphaphenazole in venous occlusion plethysmography studies had no effect on forearm blood flow in response to intrabrachial infusion of acetylcholine (Passauer et al. 2005). In human mammary arteries, EDHF is inhibited by non-specific CYP inhibitors and by 14,15-EEZE (a highly selective EET inhibitor with a structure similar to 14,15-EET; Archer et al. 2003).
Cellular proliferation
In vascular biology, cellular proliferation and migration are important factors in the progression of vascular remodelling and atherosclerosis. In human smooth muscle cells, an important proliferating cell type in atherosclerotic lesions, 11,12- and 8,9-EET induced cellular proliferation (Graber et al. 1997). Similarly, in human vascular endothelial cells, overexpression of CYP2C9 or addition of 11,12-EET increases cellular proliferation (Michaelis et al. 2003).
Migration
There are relatively fewer studies conducted in cell migration compared to the effects of epoxygenases on vascular tone. Human endothelial cells under hypoxic conditions have increased levels of CYP2C9, which is associated with a reduction in endothelial cell migration (Michaelis et al. 2005b). Confirming a antimigratory effect, Sun et al. (2002) showed that 11,12-EET significantly inhibited platelet-derived growth factor-stimulated smooth muscle cell migration by 60%. The order of efficacy was 11,12-EET < 5,6-EET = 14,15-EET <<< 8,9-EET. Overexpression of epoxygenase CYP2J2 mimicked the effects of exogenously added EETs, which was reversed by adding the epoxygenase inhibitor SKF525A.
Inflammation
Vascular disorders such as atherosclerosis have an important inflammatory component. The activity of the pro-inflammatory transcription factor nuclear factor 
B (NFB) was increased by CYP2C9 in human vascular endothelium (Fleming et al. 2001). Overexpression of CYP2C9 also increases COX-2 expression and prostaglandin E2 (PGE2) production in human vascular endothelial cells (Michaelis et al. 2005a). However, these pro-inflammatory effects of CYP2C9 may be secondary to the production of reactive oxygen species and not through the synthesis of its EETs (Fleming et al. 2001). This is supported by studies showing that exogenous addition of the EETs have anti-inflammatory effects. The EETs inhibited interleukin 1 (IL-1)- and lipopolysaccharide (LPS)-induced vasuclar cell adhesion molecule-1 (VCAM-1) expression, in the order of 11,12-EET < 8,9-EET < 5,6-EET <<< 14,15-EET (Node et al. 1999). 14,15-Epoxyeicosatrienoic acid also decreased PGE2 levels in porcine aortic smooth muscle cells by competitive inhibition of COX enzymes (Fang et al. 1998) and, considering that all EETs are substrates for COX enzymes, albeit with different affinities, they all could be capable of reducing pro-inflammatory prostaglandins. In contrast to the pro-inflammatory CYP2C9, the related family member human epoxygenase CYP2J2 does not produce reactive oxygen species. Moreover, overexpression of CYP2J2 decreased NFB activation (Node et al. 1999). Furthermore, CYP2J2 overexpression in bovine aortic endothelial cells decreased VCAM-1 transcription and expression (Node et al. 1999), which was reversed with the epoxygenase inhibitor SKF525A.
Effects on the heart
Since atherosclerosis ultimately reduces blood flow through major blood vessels, the heart is adversely affected. Moreover, the plaque or a resulting thrombus could cause occlusion of the coronary arteries, thus causing ischaemia and possible infarction. Epoxygenase enzymes also have roles in ischaemia and reperfusion, hypertrophy and hypoxia.
The epoxygenase CYP2J2 is localized to the endothelium in large and small human coronary arteries (Node et al. 1999) and is the major epoxygenase in human heart. To examine the role of CYP2J2, transgenic mice were engineered to overexpress CYP2J2 specifically in cardiac myocytes (CYP2J2Tr; Seubert et al. 2004). Hearts of CYP2J2Tr mice are anatomically and functionally normal at baseline; however, the transgenic hearts produce more 8,9-, 11,12- and 14,15-EET and have enhanced L-type Ca2+ currents (Xiao et al. 1998). Evidence for a role in controlling L-type Ca2+ channels is also seen upon addition of 5,6- and 11,12-EET, which causes an increase in cardiomyocyte shortening and an increase in intracellular Ca2+ concentration (Moffat et al. 1993). L-Type Ca2+ currents play a key role in excitation–contraction coupling in cardiac muscle (Fabiato & Fabiato, 1979), in the modulation of normal and abnormal cardiac pacemaker activity and controlling heart rate (Brown, 1982), and in the slow conduction velocities in ischaemia (Gettes & Reuter, 1974). The abnormally slow conduction in ischaemic myocardium can permit the formation of re-entry pathways in and around the ischaemic zone, leading to ventricular tachycardia, ventricular fibrillation and sudden cardiac death (Fleet et al. 1994). Since EETs affect L-type Ca2+ channels, a role for epoxygenases in ischaemic recovery is likely. Indeed, isolated, perfused hearts from CYP2J2Tr mice had significantly improved postischaemic recovery of left ventricular function, which epoxygenase inhibition completely abolished (Seubert et al. 2004). Similarly, perfusion with physiologically relevant concentrations of 11,12-EET improved postischaemic recovery in wild-type hearts (Seubert et al. 2004).
A supporting a role for CYP2J2 in ischaemia–reperfusion has also been found in studies conducted in bovine aortic and human coronary endothelial cells. Hypoxia decreases endothelial CYP2J2 expression (Yang et al. 2001), and overexpression of CYP2J2 or the addition of 11,12-EET reduces hypoxia–reoxygenation injury. Both 14,15- and 11,12-DHET are also active in attenuating the effects of hypoxia–reoygenation, albeit to a much lesser extent than 11,12-EET (Yang et al. 2001).
Epoxyeicosatrienoic acid receptors
Considerable progress has been made during the last two decades in determining the functional effects and metabolism of epoxygenases and EETs. In contrast, much less is known about the biochemical mechanisms through which EETs produce their responses. The effects of the EETs and their epoxygenase producers have been reported to occur through various different mechanisms in vascular cells, ranging from activation of ion channels to stimulation of kinases and affecting transcription. Since EETs have pleiotrophic effects, it is logical to assume that they may have a number of different receptors.
Epoxyeicosatrienoic acids as PPAR ligands?
Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear hormone receptors belonging to the steroid receptor superfamily. Their mode of action is similar to other nuclear receptors; once activated, they modulate DNA transcription by binding to promoter regions of target genes.
The PPARs are divided into three isoforms: PPAR, PPARβ/ and PPAR (Desvergne & Wahli, 1999; Moraes et al. 2006). The PPARs are expressed differentially in tissues within humans and have a wide range of effects. The PPAR isoform has been described in tissues with high metabolic activity, such as the heart, liver and kidney; it is also present in vascular and immunological cell types (see Moraes et al. 2006): endothelial cells, monocytes/macrophages, vascular smooth muscle cells and T-cells. The PPARβ/ isoform is expressed almost ubiquitously, whereas PPAR is broadly expressed in the heart, liver, lung, spleen, kidney, intestine, adrenal gland, skeletal muscle and adipose tissues, as well as in macrophages, endothelial cells, smooth muscle cells, lymphocytes and dendritic cells.
The PPARs have an ability to bind to a large number of ligands. The reason for this has been partly attributed to the large ligand-binding domain (Nolte et al. 1998; Xu et al. 1999, 2001a). The discovery of synthetic agonists of the PPARs has preceded the discovery of their endogenous ligands, with the fibrates (PPAR agonists) and the thiazolidinediones (PPAR agonists) being efficacious antihyperlipidaemic and insulin-sensitizing agents, respectively. The extensive list of ligands, ranging from synthetic compounds (e.g. rosiglitazone, GW7647 and WY-14 643) to prostaglandins (15-deoxy12,14
prostaglandin J2) and leukotrienes (LTB4), has led to the PPARs being regarded as promiscuous receptors. However, these endogenous compounds all have different binding affinities, most of which are in the high nanomolar to micromolar range, which has led to difficulty in assigning them true endogenous ligands (Bishop-Bailey & Wray, 2003). Many of the proposed endogenous ligands have originated from metabolism of AA and linoleic acid, which leads to possible endogenous ligands being produced by the epoxygenase pathway. Indeed, many of the longer term actions of the epoxygenase pathway are common to PPAR activation.
The PPAR isoform has a major role in the β-oxidation pathway in the liver (Sher et al. 1993), metabolizing lipids and lipoproteins (Duval et al. 2002). More recently, an important role in inflammation has been indicated, with multiple effects in inflammatory cells. Activation of PPAR negatively regulates the pro-inflammatory transcription factor NFB (Jones et al. 2002; Ryoo et al. 2004). The inhibition of NFB by PPAR leads to decreased expression of COX-2 in vascular smooth muscle cells (Staels et al. 1998) and decreased VCAM-1 expression in endothelial cells and vascular smooth muscle cells (Marx et al. 1999; Xu et al. 2001b).
The PPAR isoform is critical for the differentiation of preadipocytes to adipocytes and is important in glucose homeostasis (Tontonoz et al. 1994; Lehmann et al. 1995; Zhang et al. 1996); however, it too has many effects on the inflammatory response, including inhibition of NFB signalling (Ricote et al. 1998; Moraes et al. 2006). Agonists of PPAR have been shown to inhibit the activation of NFB in vascular smooth muscle cells and consequently decrease both chemokine secretion and matrix metalloproteinase expression (Chinetti et al. 2001). The PPARβ/ isoform has been less studied, but has been implicated in fatty acid oxidation in several tissues (Fredenrich & Grimaldi, 2005), as well as in inflammation. Ligands of PPARβ/ inhibited tumour necrosis factor -induced upregulation of VCAM-1 and NFB (Rival et al. 2002) and decreased COX-2 and inducible nitric oxide synthase in murine peritoneal macrophages (Welch et al. 2003).
There is therefore an overlap, in terms of both expression and effects, between epoxygenases and PPARs. There have been very few studies conducted to examine the possible candidacy of epoxygenase metabolites as PPAR ligands; however, studies conducted by Cowart et al. (2002) and Fang et al. (2006) show that CYP4A metabolism of EETs generate high-affinity PPAR ligands. Moreover, EETs generated by endothelial cells stimulated by shear stress have a paracrine anti-inflammatory effect, and inhibit NFB by activating PPAR (Liu et al. 2005).
Conclusions
In conclusion, the epoxygenase pathway generates mediators that play important roles in vascular tone and in cellular migration and proliferation, as well as in inflammation in the vasculature. Epoxyeicosatrienoic acids and their metabolites also have cardioprotective properties. As yet, a common mechanism has not been identified. However, these longer term transcriptional effects, in particular, correlate with known functions of PPAR activation, and preliminary studies have shown that the epoxygenase pathway can generate potent ligands for the PPARs. The epoxygenase–PPAR pathway may therefore represent a novel antiatherogenic, antithrombotic and cardioprotective pathway that could provide the basis for further therapeutic development in vascular and inflammatory disorders.
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Acknowledgements
Jessica Wray holds a BHF studentship (FS/04/075). David Bishop-Bailey holds a BHF Basic Science Lectureship (BS/02/002).
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