The roles of CYP450 epoxygenases and metabolites, epoxyeicosatrienoic acids, in cardiovascular and malignant diseases✩
Graphical abstract
Introduction
It is well established that arachidonic acid (AA) is converted to eicosanoid mediators by the cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) monooxygenase pathways [1]. The CYP pathway produces two types of eicosanoid products: epoxyeicosatrienoic acids (EETs), formed by CYP epoxygenases, and hydroxyeicosatetraenoic acids (HETEs), formed by CYP oxidases dependent on NADPH [2] (Fig. 1).
EETs are synthesized predominantly by the epoxygenases of the CYP2 family, including the 2C and 2J classes, although some other mammalian CYP isoforms have been reported to generate EETs (e.g., CYP1A, CYP2B, and CYP2D) [3]. To date, CYP2C8 and CYP2C9 genes in the 2C family and the CYP2J2 gene in the 2J family have been cloned and characterized in humans [4]. CYP2C and CYP2J are mainly expressed in epithelial cells, endothelial cells, smooth muscle cells, cardiomyocytes, autonomic ganglion cells, and islet cells in the heart, vessel, kidney, lung, and pancreas [5], [6], [7], [8], [9], [10], [11], [12]. Specifically, CYP2C8 is expressed mainly in the endothelium, CYP2C9 is expressed mainly in the kidney, and CYP2J2 is expressed mainly in the endothelium and myocardiocytes.
CYP2C isoforms are mainly responsible for EET biosynthesis in human liver and kidney, whereas CYP2J is the major enzyme for EET biosynthesis in heart and endothelial cells in rats and humans [9], [13]. These enzymes are localized in the endoplasmic reticulum and use AA hydrolyzed from phospholipids as a substrate when Ca2+-dependent type IV phospholipase A2 is activated and translocated from the cytosol to intracellular membranes [14], [15]. These CYP epoxygenases add an epoxide group to one of the four double bonds of AA and form four regioisomeric EETs: 5,6-, 8,9-, 11,12-, and 14,15-EET. Studies with purified CYP epoxygenases indicate that, although each enzyme is able to convert AA to all four EET regioisomers, the main products in many cases are 11,12- and 14,15-EET [16]. EETs are further converted to more stable and less bioactive metabolites, dihydroxyeicosatrienoic acids (DHETs) [17], which are easily measured in biological samples such as urine and plasma, as well as in tissues [18], [19].
Accumulating evidence indicates that EETs exhibit important, but diverse, physiological and pathophysiological roles. Over the past 2 decades, it has become increasingly evident that EETs exert many protective effects on the cardiovascular system. Recent observations revealed that forced expression of CYP2J2 and elevated levels of EETs promote tumor malignancy, including proliferation and metastasis in vivo and in vitro, but the selective inhibition of CYP2J2 attenuates these effects [19], [20], [21]. This review article highlights the progress made on determining the roles of CYP epoxygenases and their metabolites (EETs) in cardiovascular and malignant diseases. It also discusses the therapeutic potential of CYP epoxygenases and EETs, as well as the existing challenges to applying them clinically.
Section snippets
Molecular and cellular mechanisms of EETs
The molecular and cellular mechanisms through which EETs regulate various biological functions have been intensively investigated. The current understanding is that EETs may exert different biological effects via different mechanisms in different tissues and cells.
Vascular effect of EETs: vasodilation
Physiological roles of CYP epoxygenase activity in vessels are substantially EET-mediated by hyperpolarization and other mechanisms. Four regioisoforms of EETs have important vasodilator properties independent of nitric oxide (NO) and prostacyclin (PGI2) in coronary artery and peripheral vascular beds.
EETs and Tumors
The pathological consequences of cancer are related mainly to uncontrolled tumor growth and metastasis, both of which are a consequence of abnormal tumor cell proliferation, adhesion, invasion, and migration. Although angiogenesis is pivotal in the processes of wound healing and tissue regeneration, it is also implicated in the pathological growth of neoplastic tumors.
CYP epoxygenases and their derived eicosanoids promote endothelial cell proliferation, migration, and angiogenesis, as described
Summary
Rapid progress has been made in evaluating the roles of CYP epoxygenase and its metabolites, EETs, in the initiation and development of human diseases, especially cardiovascular, inflammatory, and neurological diseases. Although it remains unclear whether these effects are mediated via binding to a putative EET cell-surface and/or intracellular receptor, the collective preclinical evidence has demonstrated that potentiation of the CYP epoxygenase pathway elicits protection against various
Acknowledgments
This work was supported by funds from National Natural Science Foundation of China grants (Nos. 30930039, 30971247 and 30971248) and National Basic Research Program of China (No. 2007CB512004).
References (117)
Oxygenation of polyunsaturated fatty acids by cytochrome P450 monooxygenases
Prog. Lipid Res.
(1994)- et al.
Cytochrome P450 expression and catalytic activity in coronary arteries and liver of cattle
Biochim. Biophys. Acta BBA Gen. Subj.
(2005) - et al.
Synthesis of hydroxyeicosatetraenoic (HETEs) and epoxyeicosatrienoic acids (EETs) by cultured bovine coronary artery endothelial cells
Biochim. Biophys. Acta
(1996) - et al.
Transfection of an active cytochrome P450 arachidonic acid epoxygenase indicates that 14,15-epoxyeicosatrienoic acid functions as an intracellular second messenger in response to epidermal growth factor
J. Biol. Chem.
(1999) - et al.
Molecular cloning, expression, and functional significance of a cytochrome P450 highly expressed in rat heart myocytes
J. Biol. Chem.
(1997) - et al.
Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase
J. Lipid Res.
(2000) - et al.
Activation of Galpha s mediates induction of tissue-type plasminogen activator gene transcription by epoxyeicosatrienoic acids
J. Biol. Chem.
(2001) - et al.
Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation
J. Mol. Cell. Cardiol.
(2010) - et al.
Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function
Prog. Lipid Res.
(2004) Arachidonic acid cytochrome P450 epoxygenase pathway
J. Lipid Res.
(2009)
8,9-Epoxyeicosatrienoic acid analog protects pulmonary artery smooth muscle cells from apoptosis via ROCK pathway
Exp. Cell Res.
Epoxyeicosatrienoic acids and their sulfonimide derivatives stimulate tyrosine phosphorylation and induce mitogenesis in renal epithelial cells
J. Biol. Chem.
Cytochrome P450 epoxygenases as EDHF synthase(s)
Pharmacol. Res.
Regulation of endothelial nitric-oxide synthase activity through phosphorylation in response to epoxyeicosatrienoic acids
Prostaglandins Other Lipid Mediat.
Roles of the cytochrome P450 arachidonic acid monooxygenases in the control of systemic blood pressure and experimental hypertension
Kidney Int.
The arachidonic acid epoxygenase is a component of the signaling mechanisms responsible for VEGF-stimulated angiogenesis
Arch. Biochem. Biophys.
Characterization of 5,6- and 8,9-epoxyeicosatrienoic acids (5,6- and 8,9-EET) as potent in vivo angiogenic lipids
J. Biol. Chem.
Fibroblast growth factor-2 is a downstream mediator of phosphatidylinositol 3-kinase-Akt signaling in 14,15-epoxyeicosatrienoic acid-induced angiogenesis
J. Biol. Chem.
11,12-Epoxyeicosatrienoic acid-induced inhibition of FOXO factors promotes endothelial proliferation by down-regulating p27Kip1
J. Biol. Chem.
Cytochrome P450 2C9-induced endothelial cell proliferation involves induction of mitogen-activated protein (MAP) kinase phosphatase-1, inhibition of the c-Jun N-terminal kinase, and up-regulation of cyclin D1
J. Biol. Chem.
14, 15-Epoxyeicosatrienoic acid promotes endothelial cell dependent adhesion of human monocytic tumor U937 cells
Biochem. Biophys. Res. Commun.
11,12-epoxyeicosatrienoic acid (11,12-EET): structural determinants for inhibition of TNF-alpha-induced VCAM-1 expression
Bioorg. Med. Chem. Lett.
Synergistic effect of cytochrome P450 epoxygenase CYP2J2*7 polymorphism with smoking on the onset of premature myocardial infarction
Atherosclerosis
Arachidonic acid as a bioactive molecule
J. Clin. Invest.
Update Information on Drug Metabolism Systems Part I
Curr. Drug Metab.
Cytochrome P450 2C is an EDHF synthase in coronary arteries
Nature
Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids
Science
CYP2J subfamily cytochrome P450s in the gastrointestinal tract: expression, localization, and potential functional significance
Mol. Pharmacol.
Predominant expression of an arachidonate epoxygenase in islets of Langerhans cells in human and rat pancreas
Endocrinology
CYP2J subfamily P450s in the lung: expression, localization, and potential functional significance
Mol. Pharmacol.
Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs
J. Biochem. Mol. Toxicol.
Regulated formation of eicosanoids
J. Clin. Invest.
Prostaglandins and leukotrienes: advances in eicosanoid biology
Science
Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases
Nat. Rev. Drug Discov.
Increased CYP2J3 expression reduces insulin resistance in fructose-treated rats and db/db mice
Diabetes
Selective inhibitors of CYP2J2 related to terfenadine exhibit strong activity against human cancers in vitro and in vivo
J. Pharmacol. Exp. Ther.
Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors
Cancer Res.
Cytochrome p450 epoxygenase promotes human cancer metastasis
Cancer Res.
Evidence for a basal release of a cytochrome-related endothelium-derived hyperpolarizing factor in the radial artery in humans
Am. J. Physiol. Heart Circ. Physiol.
Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors
Circ. Res.
EETs relax airway smooth muscle via an EpDHF effect: BK(Ca) channel activation and hyperpolarization
Am. J. Physiol. Lung Cell. Mol. Physiol.
Cardiac and vascular KATP channels in rats are activated by endogenous epoxyeicosatrienoic acids through different mechanisms
J. Physiol.
Electrophysiological properties of cardiomyocytes isolated from CYP2J2 transgenic mice
Mol. Pharmacol.
Characterization of 14,15-epoxyeicosatrienoyl-sulfonamides as 14,15-epoxyeicosatrienoic acid agonists: use for studies of metabolism and ligand binding
J. Pharmacol. Exp. Ther.
Characterization of epoxyeicosatrienoic acid binding site in U937 membranes using a novel radiolabeled agonist, 20-125i-14,15-epoxyeicosa-8(Z)-enoic acid
J. Pharmacol. Exp. Ther.
Regulation of BK(Ca) channels expressed in human embryonic kidney 293 cells by epoxyeicosatrienoic acid
Mol. Pharmacol.
Epoxyeicosatrienoic acids activate K+ channels in coronary smooth muscle through a guanine nucleotide binding protein
Circ. Res.
11,12-Epoxyeicosatrienoic acid stimulates endogenous mono-ADP-ribosylation in bovine coronary arterial smooth muscle
Circ. Res.
Cytochrome P450 epoxygenases 2C8 and 2C9 are implicated in hypoxia-induced endothelial cell migration and angiogenesis
J. Cell Sci.
Action of epoxyeicosatrienoic acids on cellular function
Am. J. Physiol. Cell Physiol.
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This review is part of the Advanced Drug Delivery Reviews theme issue on " Target Cell Movement in Tumor and Cardiovascular Diseases”.