CYP-eicosanoids—A new link between omega-3 fatty acids and cardiac disease?

doi:10.1016/j.prostaglandins.2011.09.001

Prostaglandins & Other Lipid Mediators

Volume 96, Issues 1–4, November 2011, Pages 99-108

https://doi.org/10.1016/j.prostaglandins.2011.09.001 Get rights and content

Abstract

Fish oil omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protect against arrhythmia and sudden cardiac death by largely unknown mechanisms. Recent in vitro and in vivo studies demonstrate that arachidonic acid (AA) metabolizing cytochrome P450-(CYP) enzymes accept EPA and DHA as efficient alternative substrates. Dietary EPA/DHA supplementation causes a profound shift of the cardiac CYP-eicosanoid profile from AA- to EPA- and DHA-derived epoxy- and hydroxy-metabolites. CYP2J2 and other CYP epoxygenases preferentially epoxidize the ω-3 double bond of EPA and DHA. The corresponding metabolites, 17,18-epoxy-EPA and 19,20-epoxy-DHA, dominate the CYP-eicosanoid profile of the rat heart after EPA/DHA supplementation. The (ω-3)-epoxyeicosanoids show highly potent antiarrhythmic properties in neonatal cardiomyocytes, suggesting that these metabolites may specifically contribute to the cardioprotective effects of omega-3 fatty acids. This hypothesis is discussed in the context of recent findings that revealed CYP-eicosanoid mediated mechanisms in cardiac ischemia–reperfusion injury and maladaptive cardiac hypertrophy.

Highlights

► EPA and DHA protect against arrhythmia and sudden cardiac death. ► CYP enzymes efficiently hydroxylate and epoxidize EPA and DHA. ► Dietary EPA/DHA supplementation modulates the cardiac CYP eicosanoid profile. ► CYP-dependent (ω-3)-epoxyeicosanoids exhibit potent antiarrhythmic properties. ► (ω-3)-Epoxyeicosanoids may mediate cardioprotective signaling pathways.

Section snippets

Omega-3 fatty acids and cardiac disease

Epidemiological, clinical and experimental studies suggest that long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) protect against cardiovascular disease [1], [2], [3], [4]. In particular, n-3 PUFAs reduce the mortality from coronary heart disease and the rate of sudden cardiac death [5], [6]. Strong antiarrhythmic effects of n-3 PUFAs were demonstrated in animal models of ventricular tachyarrhythmia [7], [8], [9] as well as atrial fibrillation [10], [11]. Protection against ventricular

Molecular mechanisms of n-3 PUFA action

The numerous cardiovascular health benefits of n-3 PUFAs are mediated by multiple and thus far only partially understood mechanisms at the molecular level (Table 1). As outlined above, mechanistic diversity is already indicated by the different dose- and time-dependencies of the antiarrhythmic, hypolipidemic, antithrombotic and other physiological effects exerted by EPA/DHA supplementation [19]. Moreover, some of the biological activities of n-3 PUFAs depend on their incorporation into cellular

Metabolism of EPA and DHA by cytochrome P450 enzymes

CYP enzymes initiate the so-called third branch of eicosanoid formation [34], [35], [36], [37]. Studies establishing the cardiovascular role of this pathway were almost exclusively focused on AA as the precursor of biologically active CYP metabolites. However, recent studies demonstrate that virtually all CYP enzymes, previously considered as AA monooxygenases, accept EPA and DHA as efficient alternative substrates (Table 2). CYP enzymes produce biologically active epoxy- and

Effect of dietary EPA/DHA supplementation on the cardiac CYP-eicosanoid profile

Data are rare that demonstrate the extent and significance of CYP-dependent EPA/DHA metabolism under in vivo conditions. First evidence was provided by the detection of EEQs and EDPs in human urine and plasma samples [43], [44]. We performed a systematic study in rat in order to analyze the effects of EPA/DHA supplementation on the fatty acid and CYP-eicosanoid profiles in various tissues and organs [41]. The rats received two types of dietary fat: (i) sunflower oil alone to provide an n-6

Role of CYP-eicosanoids in cardiac disease

Resembling the biosynthesis of other eicosanoid classes, de novo synthesis of CYP-eicosanoids requires molecular oxygen and the presence of nonesterified parental PUFAs. Specifically, the CYP enzymes are additionally dependent on NADPH for catalyzing the monooxygenation reactions [45]. Thus, de novo synthesis of CYP-eicosanoids proceeds under normoxic conditions and is initiated by extracellular signal-induced activation of PLA2 enzymes that release AA, EPA and DHA from the sn-2 position of

Molecular mechanisms of CYP-eicosanoid action in the heart

The cardioprotective role of EETs is probably based on a combination of the antiinflammatory, antihypertrophic and antiapoptotic effects exerted by this class of CYP-eicosanoids. The capacity of EETs to inhibit pro-inflammatory transcription factor NF-κB activation was shown in endothelial cells [72], cardiomyocytes [66] and fibroblasts [73]. EET-mediated inhibition of NF-κB activation is likely also the key for understanding the antihypertrophic effects of sEH-inhibition in models of Ang II-

Potential antiarrhythmic properties of omega-3 epoxyeicosanoids

Currently, it is largely unclear whether or not the cardioprotective mechanisms attributed to EETs are shared by the CYP-epoxyeicosanoids derived from EPA and DHA. Suggesting in part superior biological activities, the capacity of EETs to activate K_ATP channels in cardiomyocytes is largely exceeded by their EPA- and DHA-derived counterparts [92]. In the vasculature, EEQs and EDPs share and partially strongly exceed the vasodilatory properties of EETs [93], [94], [95], [96]. Lung studies with

Conclusions and hypothesis

The findings summarized above demonstrate that EPA and DHA are efficient alternative substrates of AA metabolizing CYP enzymes both under in vitro and in vivo conditions. On the one hand, these findings may have been expected since many CYP enzymes exhibit rather broad substrate specificities. On the other hand, this “promiscuity” of CYP enzymes makes CYP-eicosanoid signaling probably even more susceptible to changes in the n-6/n-3 PUFA ratio as described before for the COX- and LOX-dependent

Acknowledgment

This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG): Schu822/5; FOR 1054.

References (115)

C.J. Lavie et al.
Omega-3 polyunsaturated fatty acids and cardiovascular diseases
J Am Coll Cardiol
(2009)
D. Mozaffarian
Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death
Am J Clin Nutr
(2008)
N.R. Matthan et al.
A systematic review and meta-analysis of the impact of omega-3 fatty acids on selected arrhythmia outcomes in animal models
Metabolism
(2005)
J.F. Sarrazin et al.
Reduced incidence of vagally induced atrial fibrillation and expression levels of connexins by n-3 polyunsaturated fatty acids in dogs
J Am Coll Cardiol
(2007)
L. Calo et al.
N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial
J Am Coll Cardiol
(2005)
J. Dyerberg et al.
Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis?
Lancet
(1978)
L.M. Arterburn et al.
Distribution, interconversion, and dose response of n-3 fatty acids in humans
Am J Clin Nutr
(2006)
W.S. Harris
The omega-3 index as a risk factor for coronary heart disease
Am J Clin Nutr
(2008)
D.Y. Oh et al.
GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects
Cell
(2010)
M. Wada et al.
Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products
J Biol Chem
(2007)

M. Shikano et al.

Complete discrimination of docosahexaenoate from arachidonate by 85 kDa cytosolic phospholipase A2 during the hydrolysis of diacyl- and alkenylacylglycerophosphoethanolamine

Biochim Biophys Acta

(1994)

S.I. Rapoport

Brain arachidonic and docosahexaenoic acid cascades are selectively altered by drugs, diet and disease

Prostaglandins Leukot Essent Fatty Acids

(2008)

A.O. Rosa et al.

Intracellular- and extracellular-derived Ca(2+) influence phospholipase A(2)-mediated fatty acid release from brain phospholipids

Biochim Biophys Acta

(2009)

T. Terano et al.

Biosynthesis and biological activity of leukotriene B5

Prostaglandins

(1984)

D.B. Jump

The biochemistry of n-3 polyunsaturated fatty acids

J Biol Chem

(2002)

J.H. Capdevila et al.

Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase

J Lipid Res

(2000)

D.C. Zeldin

Epoxygenase pathways of arachidonic acid metabolism

J Biol Chem

(2001)

A. Konkel et al.

Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids

Biochim Biophys Acta

(2011)

E. Barbosa-Sicard et al.

Eicosapentaenoic acid metabolism by cytochrome P450 enzymes of the CYP2C subfamily

Biochem Biophys Res Commun

(2005)

M. Fer et al.

Metabolism of eicosapentaenoic and docosahexaenoic acids by recombinant human cytochromes P450

Arch Biochem Biophys

(2008)

D. Lucas et al.

Stereoselective epoxidation of the last double bond of polyunsaturated fatty acids by human cytochromes P450

J Lipid Res

(2010)

H.R. Knapp et al.

Urinary excretion of diols derived from eicosapentaenoic acid during n-3 fatty acid ingestion by man

Prostaglandins

(1991)

G.C. Shearer et al.

Detection of omega-3 oxylipins in human plasma and response to treatment with omega-3 acid ethyl esters

J Lipid Res

(2010)

J.H. Capdevila et al.

Biochemical and molecular properties of the cytochrome P450 arachidonic acid monooxygenases

Prostaglandins Other Lipid Mediat

(2002)

D.C. Zeldin et al.

Regio- and enantiofacial selectivity of epoxyeicosatrienoic acid hydration by cytosolic epoxide hydrolase

J Biol Chem

(1993)

D.C. Zeldin et al.

Metabolism of epoxyeicosatrienoic acids by cytosolic epoxide hydrolase: substrate structural determinants of asymmetric catalysis

Arch Biochem Biophys

(1995)

A. Karara et al.

Endogenous epoxyeicosatrienoyl-phospholipids. A novel class of cellular glycerolipids containing epoxidized arachidonate moieties

J Biol Chem

(1991)

J.H. Capdevila et al.

Roles of the cytochrome P450 arachidonic acid monooxygenases in the control of systemic blood pressure and experimental hypertension

Kidney Int

(2007)

I. Fleming

Vascular cytochrome p450 enzymes: physiology and pathophysiology

Trends Cardiovasc Med

(2008)

J.M. Seubert et al.

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

Prostaglandins Other Lipid Mediat

(2007)

S. Wu et al.

Molecular cloning, expression, and functional significance of a cytochrome P450 highly expressed in rat heart myocytes

J Biol Chem

(1997)

S.N. Batchu et al.

Epoxyeicosatrienoic acid prevents postischemic electrocardiogram abnormalities in an isolated heart model

J Mol Cell Cardiol

(2009)

G.J. Gross et al.

Mechanisms by which epoxyeicosatrienoic acids (EETs) elicit cardioprotection in rat hearts

J Mol Cell Cardiol

(2007)

K. Nithipatikom et al.

Determination of cytochrome P450 metabolites of arachidonic acid in coronary venous plasma during ischemia and reperfusion in dogs

Anal Biochem

(2001)

E.R. Gross et al.

Cytochrome P450 omega-hydroxylase inhibition reduces infarct size during reperfusion via the sarcolemmal K_ATP channel

J Mol Cell Cardiol

(2004)

S. Bodiga et al.

Protective actions of epoxyeicosatrienoic acid: dual targeting of cardiovascular PI3K and K_ATP channels

J Mol Cell Cardiol

(2009)

D. Katragadda et al.

Epoxyeicosatrienoic acids limit damage to mitochondrial function following stress in cardiac cells

J Mol Cell Cardiol

(2009)

Y.F. Xiao

Cyclic AMP-dependent modulation of cardiac L-type Ca²⁺ and transient outward K+ channel activities by epoxyeicosatrienoic acids

Prostaglandins Other Lipid Mediat

(2007)

D.J. Hausenloy et al.

The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and postconditioning

Trends Cardiovasc Med

(2005)

N. Li et al.

Beneficial effects of soluble epoxide hydrolase inhibitors in myocardial infarction model: insight gained using metabolomic approaches

J Mol Cell Cardiol

(2009)

J.X. Kang et al.

Prevention and termination of beta-adrenergic agonist-induced arrhythmias by free polyunsaturated fatty acids in neonatal rat cardiac myocytes

Biochem Biophys Res Commun

(1995)

P.M. Kris-Etherton et al.

Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease

Circulation

(2002)

R. De Caterina

n-3 fatty acids in cardiovascular disease

N Engl J Med

(2011)

W.E. Lands

Dietary fat and health: the evidence and the politics of prevention: careful use of dietary fats can improve life and prevent disease

Ann N Y Acad Sci

(2005)

A. Leaf et al.

Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils

Circulation

(2003)

R. Fischer et al.

Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electrical remodeling in a model of high human renin hypertension

Hypertension

(2008)

J.Y. Gao et al.

Long-term treatment with eicosapentaenoic acid ameliorates myocardial ischemia–reperfusion injury in pigs in vivo

Circ J

(2011)

K. Kitamura et al.

Eicosapentaenoic acid prevents atrial fibrillation associated with heart failure in a rabbit model

Am J Physiol Heart Circ Physiol

(2011)

R. Marchioli et al.

Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione

Circulation

(2002)

J.K. Virtanen et al.

Serum long-chain n-3 polyunsaturated fatty acids and risk of hospital diagnosis of atrial fibrillation in men

Circulation

(2009)

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Cytochromes P450 metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which have numerous effects. After cardiac ischemia, EET-induced coronary vasodilation increases delivery of oxygen/nutrients to the myocardium, and EET-induced signaling protects cardiomyocytes against postischemic mitochondrial damage. Soluble epoxide hydrolase 2 (EPHX2) diminishes the benefits of EETs through hydrolysis to less active dihydroxyeicosatrienoic acids. EPHX2 inhibition or genetic disruption improves recovery of cardiac function after ischemia. Immunohistochemical staining revealed EPHX2 expression in cardiomyocytes and some endothelial cells but little expression in cardiac smooth muscle cells or fibroblasts. To determine specific roles of EPHX2 in cardiac cell types, we generated mice with cell-specific disruption of Ephx2 in endothelial cells (Ephx2^fx/fx/Tek-cre) or cardiomyocytes (Ephx2^fx/fx/Myh6-cre) to compare to global Ephx2-deficient mice (global Ephx2^−/−) and WT (Ephx2^fx/fx) mice in expression, EET hydrolase activity, and heart function studies. Most cardiac EPHX2 expression and activity is in cardiomyocytes with substantially less activity in endothelial cells. Ephx2^fx/fx/Tek-cre hearts have similar EPHX2 expression, hydrolase activity, and postischemic cardiac function as control Ephx2^fx/fx hearts. However, Ephx2^fx/fx/Myh6-cre hearts were similar to global Ephx2^−/− hearts with significantly diminished EPHX2 expression, decreased hydrolase activity, and enhanced postischemic cardiac function compared to Ephx2^fx/fx hearts. During reperfusion, Ephx2^fx/fx/Myh6-cre hearts displayed increased ERK activation compared to Ephx2^fx/fx hearts, which could be reversed by EEZE treatment. EPHX2 did not regulate coronary vasodilation in this model. We conclude that EPHX2 is primarily expressed in cardiomyocytes where it regulates EET hydrolysis and postischemic cardiac function, whereas endothelial EPHX2 does not play a significant role in these processes.
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Endothelial cells are characterized by intense metabolic activity and control of homeostasis. Exposure to benzo(a)pyrene (BaP) plays an important role in the etiology of atherosclerosis. The study aimed to determine the effect of arachidonic (ARA), and eicosapentaenoic acid (EPA) on pro-inflammatory gene and protein levels in human umbilical vein endothelial cells (HUVEC) exposed to BaP. Cyclooxygenase-2 (COX-2), aryl hydrocarbon receptor (AHR), and glutathione S transferase Mu1 (GSTM1) proteins expression were analyzed by Western blot. Prostaglandin synthase 2 (PTGS2), AHR, GSTM1, phospholipase A2 (PLA2G4A), cytochrome P450 CYP1A1, intercellular adhesion molecule-1 (ICAM-1), endothelial nitric-oxide synthase (NOS3), and vascular adhesion molecule-1 gene expression (VCAM-1) was analyzed in Real time-qPCR. Phospholipase A2 activity was measured using the ELISA technique, and CYP1A1 activity was analyzed in luminescence assay.
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ReviewCYP-eicosanoids—A new link between omega-3 fatty acids and cardiac disease?

Abstract

Highlights

Section snippets

Omega-3 fatty acids and cardiac disease

Molecular mechanisms of n-3 PUFA action

Metabolism of EPA and DHA by cytochrome P450 enzymes

Effect of dietary EPA/DHA supplementation on the cardiac CYP-eicosanoid profile

Role of CYP-eicosanoids in cardiac disease

Molecular mechanisms of CYP-eicosanoid action in the heart

Potential antiarrhythmic properties of omega-3 epoxyeicosanoids

Conclusions and hypothesis

Acknowledgment

J Am Coll Cardiol

Am J Clin Nutr

Metabolism

J Am Coll Cardiol

J Am Coll Cardiol

Lancet

Am J Clin Nutr

Am J Clin Nutr

Cell

J Biol Chem

Biochim Biophys Acta

Prostaglandins Leukot Essent Fatty Acids

Biochim Biophys Acta

Prostaglandins

J Biol Chem

J Lipid Res

J Biol Chem

Biochim Biophys Acta

Biochem Biophys Res Commun

Arch Biochem Biophys

J Lipid Res

Prostaglandins

J Lipid Res

Prostaglandins Other Lipid Mediat

J Biol Chem

Arch Biochem Biophys

J Biol Chem

Kidney Int

Trends Cardiovasc Med

Prostaglandins Other Lipid Mediat

J Biol Chem

J Mol Cell Cardiol

J Mol Cell Cardiol

Anal Biochem

J Mol Cell Cardiol

J Mol Cell Cardiol

J Mol Cell Cardiol

Prostaglandins Other Lipid Mediat

Trends Cardiovasc Med

J Mol Cell Cardiol

Biochem Biophys Res Commun

Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease

Circulation

n-3 fatty acids in cardiovascular disease

N Engl J Med

Dietary fat and health: the evidence and the politics of prevention: careful use of dietary fats can improve life and prevent disease

Ann N Y Acad Sci

Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils

Circulation

Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electrical remodeling in a model of high human renin hypertension

Hypertension

Long-term treatment with eicosapentaenoic acid ameliorates myocardial ischemia–reperfusion injury in pigs in vivo

Circ J

Eicosapentaenoic acid prevents atrial fibrillation associated with heart failure in a rabbit model

Am J Physiol Heart Circ Physiol

Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione

Circulation

Serum long-chain n-3 polyunsaturated fatty acids and risk of hospital diagnosis of atrial fibrillation in men

Circulation

Review
CYP-eicosanoids—A new link between omega-3 fatty acids and cardiac disease?