Journal of Cardiology 67 (2016) 22–27

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Journal of Cardiology
journal homepage: www.elsevier.com/locate/jjcc

Review

Cardioprotective mechanism of omega-3 polyunsaturated fatty acids

Jin Endo (MD, PhD)a,*, Makoto Arita (PhD)b,c,**
a
Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
b
Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
c
Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid and docosahexaenoic acid,
Received 31 July 2015 are widely regarded as cardioprotective. Several large-scale, randomized clinical trials have shown that
Accepted 31 July 2015 dietary intake of omega-3 PUFAs improves the prognosis of patients with symptomatic heart failure or
Available online 8 September 2015
recent myocardial infarction. Therefore, dietary consumption of omega-3 PUFA is recommended in
international guidelines for the general population to prevent the occurrence of cardiovascular diseases
Keywords: (CVDs). However, the precise mechanisms underlying the cardioprotective effects of omega-3 PUFAs are
Omega-3 polyunsaturated fatty acids
not fully understood. Omega-3 PUFAs can be incorporated into the phospholipid bilayer of cell
Cardiovascular disease
Anti-inflammation
membranes and can affect membrane fluidity, lipid microdomain formation, and signaling across
Specialized proresolving mediators membranes. Omega-3 PUFAs also modulate the function of membrane ion channels, such as Na and
18-Hydroxyeicosapentaenoic acid L-type Ca channels, to prevent lethal arrhythmias. Moreover, omega-3 PUFAs also prevent the
conversion of arachidonic acid into pro-inflammatory eicosanoids by serving as an alternative substrate
for cyclooxygenase or lipoxygenase, resulting in the production of less potent products. In addition, a
number of enzymatically oxygenated metabolites derived from omega-3 PUFAs were recently identified
as anti-inflammatory mediators. These omega-3 metabolites may contribute to the beneficial effects
against CVDs that are attributed to omega-3 PUFAs.
ß 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Modification of the cell membrane milieu by incorporation of omega-3 PUFAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Anti-arrhythmic effects of omega-3 PUFAs due to ion channel modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
The anti-inflammatory effects of omega-3 PUFAs mediated by nuclear receptors, G-protein coupled receptors, and other mechanisms . . . 24
Novel bioactive lipid mediators of omega-3 PUFAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Novel beneficial effects of a macrophage-derived EPA metabolite, 18-HEPE, on cardiac remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

* Corresponding author at: Department of Cardiology, Keio University School of
Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Tel.: +81 3 5363 3874; fax: +81 3 5363 3875.
** Corresponding author at: Laboratory for Metabolomics, RIKEN Center for
Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama
City, Kanagawa 230-0045, Japan. Tel.: +81 45 503 7055; fax: +045 503 7054.
E-mail addresses: jinendo@keio.jp (J. Endo), makoto.arita@riken.jp
(M. Arita).
Introduction
The beneficial effects of n-3 polyunsaturated fatty acids
(PUFAs), primarily eicosapentaenoic acid (EPA) and docosahex-
aenoic acid (DHA), were first recognized in the late 1960s when
epidemiological evidence from the Inuit population, who consume
an n-3 PUFA-rich diet, showed that they have a low incidence
of myocardial infarction [1]. Subsequently, a large number

http://dx.doi.org/10.1016/j.jjcc.2015.08.002
0914-5087/ß 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
 J. Endo, M. Arita / Journal of Cardiology 67 (2016) 22–27
of randomized clinical trials have investigated the efficacy of
supplementation with fish oil or omega-3 PUFAs. The GISSI-
Prevenzione trial [2] was the first large-scale, randomized trial to
provide evidence that dietary supplementation with omega-3
PUFAs had favorable effects on hard clinical end-points in post-
myocardial infarction patients. The GISSI-HF trial [3] also showed
that omega-3 PUFAs could reduce morbidity and mortality in
patients with symptomatic chronic heart failure who were
receiving standard treatments, including aspirin, beta-blockers,
angiotensin-converting enzyme inhibitor/angiotensin receptor
blockers, and aldosterone receptor blockers. Further, the JELIS
study [4], a randomized large trial conducted in Japan, revealed
that treatment with a pharmaceutical preparation of highly
purified EPA in addition to statin significantly prevented cardio-
vascular events in patients with recent myocardial infarction
through an apparently cholesterol-independent mechanism. The
results of the above-mentioned studies showed that omega-3
PUFA treatment is safe and well tolerated, and the clinical
improvements observed were additive to those of other well-
established therapies. Therefore, in a scientific statement from the
American Heart Association, the consumption of >1 g/day of
omega-3 PUFAs (EPA+DHA; this dose was largely determined from
the results of the GISSI-Prevenzione study) was recommended for
patients with coronary artery disease to reduce triglyceride (TG)
levels, maintain cardiac function, and reduce the risk of coronary
heart disease [5]. In addition, many animal studies have
demonstrated that omega-3 PUFAs have pleiotropic beneficial
effects in the cardiovascular system, including anti-arrhythmic,
plasma TG-lowering, anti-thrombotic, anti-atherosclerotic, endo-
thelial relaxation, blood pressure-lowering, anti-inflammatory,
and anti-fibrotic effects [6]. In this review, we present recent
advances in our understanding of the molecular mechanisms
underlying the cardioprotective effects of omega-3 PUFAs.
[(Fig._1)TD$IG]
Fig. 1. The proposed molecular mechanism of cardioprotection by omega-3 PUFAs. Omega-3 PUFAs modulate cell membrane property when incorporated into the
phospholipid bilayer and control membrane ion channels to prevent lethal arrhythmia. Also omega-3 PUFAs exert anti-inflammatory and anti-fibrotic effects by modifying
NF-kB signaling, the NLRP3 inflammasome, PPARa/g, GPR120, and TGF-b signaling.
NF-kB: nuclear factor-kB; NLRP3: NOD-like receptor family, pyrin domain containing 3; PPARa/g: peroxisome proliferator-activated receptor a/g; GPR120: G protein-
coupled receptor 120; TGF-b: transforming growth factor-b.
23
Modification of the cell membrane milieu by incorporation of
omega-3 PUFAs
The cell membrane is composed of phospholipids (PLs) that
contain various types of fatty acids. The length and saturation of
the fatty acids in these PLs is thought to affect the properties of cell
membranes by altering the microdomain ‘‘rafts’’ and ‘‘caveolae’’
that concentrate membrane proteins and lipids and function as
signaling platforms. Since omega-3 PUFAs have many double
bonds and long-chain carbons, their incorporation into the PLs
within a membrane can alter its properties and influence the
function of various membrane proteins (Fig. 1), including the
suppression of protein kinase C theta signaling and interleukin (IL)-
2 production [7], and the disruption of dimerization and
recruitment of toll-like receptor 4 [8]. Of note, alteration of the
lipid microenvironment in cardiomyocytes through the inclusion
of omega-3 PUFAs can modulate ion channel function, leading to
anti-arrhythmic effects [6].
Anti-arrhythmic effects of omega-3 PUFAs due to ion channel
modulation
The clinical outcomes of several trials, including GISSI-
Prevenzione, have suggested that omega-3 PUFAs might prevent
the occurrence of sudden cardiac death triggered by lethal
arrhythmias. Accumulating evidence from in vivo and in vitro
experiments has demonstrated that omega-3 PUFAs exert anti-
arrhythmic effects through modulation of myocyte electrophysi-
ology. Omega-3 PUFAs reduce the activity of membrane sodium
channels in cardiomyocytes, thus increasing the threshold for
membrane potential depolarization [9]. EPA and DHA also
modulate the activity of L-type calcium channels, leading to a
reduction in free cytosolic calcium ion, which stabilizes myocyte
24 J. Endo, M. Arita / Journal of Cardiology 67 (2016) 22–27
electrical excitability to prevent fatal arrhythmia [10]. EPA blocks
the sodium-calcium channel; however, a single amino-acid point
mutation in this channel attenuated the inhibitory effect of EPA
[11]. These findings suggested that the cardioprotective effect of n-
3 PUFAs is mediated by direct interaction with membrane ion
channels (Fig. 1).
The anti-arrhythmic effects of omega-3 PUFAs, which occur by
blocking various ion channels, are encouraging. In fact, the results
of several trials have suggested that dietary supplementation with
omega-3 PUFAs might be an effective optional therapy for
arrhythmias. However, the FORWARD trial, a prospective, ran-
domized, clinical trial, found that treatment with omega-3 PUFAs
over a 6-month period did not reduce recurrent symptomatic atrial
fibrillation [12]. In the specific study population with paroxysmal
atrial fibrillation (AF), it was concluded that omega-3 PUFAs are
not a useful treatment. These results do not exclude the potential
anti-arrhythmic effects of prescription omega-3 PUFAs in combi-
nation with antiarrhythmic drugs in different populations, such as
patients with heart failure; however, validation in prospective
trials is required.
The anti-inflammatory effects of omega-3 PUFAs mediated by
nuclear receptors, G-protein coupled receptors, and other
mechanisms
Acute and chronic inflammation underlie the pathogenesis and
progression of various cardiovascular diseases (CVDs), including
myocarditis, myocardial infarction, aortic dissection, atheroscle-
rosis, and cardiac remodeling. It is widely believed that the anti-
inflammatory properties of omega-3 PUFAs contribute to their
cardioprotective effects. In fact, dietary intake of omega-3 PUFAs
was reported to decrease the circulating concentrations of
inflammatory cytokines such as tumor necrosis factor (TNF), IL-
1b, and IL-6, and ameliorate left ventricular functional capacity in
non-ischemic dilated cardiomyopathy [13].
EPA and DHA downregulate the expression of inflammation-
[(Fig._2)TD$IG]
related genes through inhibition of NF-kB signaling by blocking
Fig. 2. Anti-inflammatory effects of omega-3 PUFAs through mediator balance. The anti-inflammatory effects of omega-3 PUFAs are attributed to (1) prevention of the
conversion of AA into PGs and LTs or (2) its ability to function as an alternative substrate to produce less potent mediators. (3) Resolvins, protectins, and maresins, distinct
anti-inflammatory and pro-resolving lipid mediators derived from omega-3 PUFAs.
AA: arachidonic acid; PGs: prostaglandins; LTs: leukotrienes.
IkB phosphorylation [14] (Fig. 1) or through the nuclear receptor
PPARa/g [15] (Fig. 1). In addition, omega-3 PUFA is a ligand for
GPR120, which attenuates both toll-like receptor 4- and TNF-a-
mediated proinflammatory signaling in macrophages [16] (Fig. 1).
GPR120, a member of the GPCR family, is also highly expressed in
mature adipocytes, and GPR120 stimulation with omega-3 PUFAs
was shown to augment GLUT4 glucose transporter expression to
promote glucose uptake in adipocytes [16]. Chronic tissue
inflammation is a well-known cause of insulin resistance. In a
mouse obesity model, the anti-inflammatory and insulin-sensitiz-
ing effects of omega-3 PUFAs were shown to be dependent on the
expression of GPR120, and administration of a selective agonist
improved insulin resistance [17]. NOD-like receptor family, pyrin
domain-containing 3 (NLRP3) senses non-microbial danger signals
and forms an inflammasome, leading to a sterile inflammatory
response in myocardial infarction, ischemia reperfusion injury, and
pressure overload-induced cardiac remodeling. Omega-3 PUFAs
prevented NLRP3 inflammasome-dependent inflammation and
metabolic disorder in HFD-induced diabetic mice [18] (Fig. 1).
Moreover, EPA and DHA directly reduced cardiac fibrosis under
pressure overload by inhibiting TGF-b1-induced smad2/3 nuclear
translocation, a major pathway involved in the development of
cardiac remodeling [19] (Fig. 1). EPA and DHA increased nitric
oxide production and promoted subsequent activation of the cyclic
GMP/PKG pathway in cardiac fibroblasts. Taken together, these
findings suggest that omega-3 PUFAs may have both anti-
inflammatory and anti-fibrotic properties.
Novel bioactive lipid mediators of omega-3 PUFAs
Since the 1970s, the beneficial effects of omega-3 PUFAs have
been commonly explained to be attributed to either prevention of
the conversion of the omega-6 PUFA arachidonic acid (AA) into
pro-inflammatory prostaglandins (PGs) and leukotrienes (LTs), or
its ability to serve as an alternative substrate, producing less potent
mediators, such as 3-series PGs and thromboxanes (TXs) and
5-series LTs (Fig. 2). For instance, the lower incidence of myocardial
 J. Endo, M. Arita / Journal of Cardiology 67 (2016) 22–27 25

infarction in a population that consumed a diet rich in omega-3
PUFAs could be due, in part, to a reduction in the formation of the
pro-thrombotic prostanoid TXA2 from AA. Moreover, omega-3
PUFAs are metabolized to PGI3, which possesses anti-platelet
effects, and TXA3, which does not induce platelet aggregation [20].
Liquid chromatography–mass spectrometry (LC–MS)-based
lipidomic analyses of murine inflammatory exudates or activated
cell supernatants have identified distinct omega-3 PUFA-derived
pro-resolving mediators, such as resolvins, protectins, and
maresins [21] (Fig. 2). They possess distinct chemical structures
and exert their anti-inflammatory effects in a stereospecific
manner. These mediators are now generally termed specialized
pro-resolving mediators (SPMs). Resolvin E series are synthesized
from EPA through the conversion of 18-hydroxyeicosapentaenoic
acid (18-HEPE) by aspirin-acetylated COX2 or CYP450 monoox-
ygenase. RvE1 actively switches off leukocyte trafficking to the
inflamed site, promotes the clearance of inflammatory cells and
debris, and suppresses cytokine production, thereby leading to
resolution of acute inflammation [21]. In addition, RvE1 can inhibit
platelet aggregation by ADP or TXA2 receptor activation [21].
DHA-derived mediators, such as protectins, resolvin D-series,
and maresins, are generated by 15-LOX in humans or by 12/15-
LOX in mice. PD1 exhibits protective effects against brain
ischemia, resistance to retinal oxidative injury, and protection
against renal ischemia/reperfusion injury [21]. RvD1 is shown to
be protective in various disease models, such as insulin resistance,
atherosclerosis, ischemia reperfusion, and others [21]. In addition,
RvD2 could reduce the damage and subsequent scarring of
kidneys after ischemia/reperfusion [21]. PD1 and RvD1 have been
shown to reduce pathogenic neovascularization in murine
oxygen-induced retinopathy [21]. Furthermore, a recent report
showed that administration of PD1 isomer (PDX) improved
insulin sensitivity in obese diabetic db/db mice, suggesting that
this SPM possesses therapeutic potential for the treatment of
metabolic disorders [22].
Atherosclerosis is now commonly recognized as an unresolved
inflammatory disease involving the vascular wall. Therefore, it is
assumed that the pathogenesis of atherosclerosis involves a
decrease in SPM production; thus, SPM replacement could control
[(Fig._3)TD$IG] local inflammatory response and improve the atherosclerotic
the
changes. One study showed that 12/15-LOX is protective against
atherosclerosis through the production of SPMs including RvD1
and PD1, which could attenuate the local inflammatory response in
macrophages and endothelial cells [23]. Hasturk et al. found that
oral-topical application of RvE1 reduced atherogenesis induced by
both diet and periodontal inflammation and could prevent the
systemic inflammatory response and aortic atherosclerosis in the
absence of periodontitis [24].
There is accumulating evidence demonstrating that SPMs
directly exert cardioprotective actions in vivo. Keyes et al. [25]
reported that administration of RvE1 attenuated the infarct size in
rats subjected to ischemia/reperfusion injury. The results of this
study suggested that RvE1 directly affected cardiomyocytes and
protected against cardiac injury. In addition, Kain et al. [26]
showed that treatment with RvD1 accelerated the resolution of
acute inflammation following myocardial infarction by promoting
the production of SPM in the spleen and switching to anti-
inflammatory M2 macrophages in the left ventricle, which
prevented cardiac fibrosis and preserved cardiac function.
PUFAs are oxidized by CYP450 monooxygenase to epoxides,
which function as potent lipid mediators in the cardiovascular
system. The epoxyeicosatrienoic acids (EETs) generated from AA
induce vasodilation, stimulate angiogenesis, and protect the heart
from ischemia/reperfusion injury. CYP450 monooxygenase also
converts EPA and DHA to epoxyeicosatetraenoic acids (EpETEs)
and epoxydocosapentaenoic acids (EpDPAs), respectively, which
function as lipid mediators similar to EET. By activating BK
channels, 17(18)-EpETE dilates human pulmonary arteries and
16(17)-EpDPA activates rat coronary smooth muscle [27]. Omega-
3 PUFA-derived epoxides possess anti-inflammatory properties in
the setting of CVD. The increased EpETE and EpDPA levels
following dietary administration of omega-3 PUFAs reduced the
renal markers of inflammation in angiotensin II-dependent
hypertension [27]. EpETEs and EpDPAs protect the heart through
their anti-arrhythmic actions. Recent studies are focusing on the
development of stable epoxide bioisosteric analogs and soluble
epoxide hydrolase inhibitors that can stabilize epoxides by
inhibiting their hydrolysis to the corresponding diols in order
to potentiate their functional effects and for use as novel
therapeutics against CVD [28].

Fig. 3. An EPA metabolite, 18-HEPE, from cardiac macrophages rich in omega-3 PUFAs prevents cardiac remodeling under pressure overload. Activated cardiac
fibroblasts, namely myofibroblasts, produce pro-inflammatory mediators that facilitate cardiac macrophage activation. Cardiac fibroblasts can be activated directly by
pressure overload or secondarily by inflammatory mediators released from activated inflammatory cells. EPA-enriched macrophages generate an 18-HEPE-rich milieu in the
heart, thereby discontinue the profibrotic feed-forward loop that is involved in the development of cardiac fibrosis under pressure overload.
EPA: eicosapentaenoic acid; 18-HEPE: 18-hydroxy eicosapentaenoic acid.
26 J. Endo, M. Arita / Journal of Cardiology 67 (2016) 22–27
Novel beneficial effects of a macrophage-derived EPA
metabolite, 18-HEPE, on cardiac remodeling
Recently, we identified a novel anti-inflammatory and anti-
fibrotic EPA metabolite, 18-HEPE, and elucidated the mechanism
underlying omega-3 PUFA-mediated prevention of cardiac remo-
deling under pressure overload [29] (Fig. 3). Kang et al. developed a
transgenic mouse expressing the Caenorhabditi elegans fat-1 gene,
which encodes an omega-3 desaturase that converts omega-6
PUFAs to omega-3 PUFAs [30]. Fat-1 mice showed enrichment of
omega-3 PUFAs in almost all cells and tissues, and displayed
resistance to numerous inflammatory diseases, including colitis,
pancreatitis, osteoarthritis, atherosclerosis, obesity-linked insulin
resistance, and some cancers [31]. Compared to wild-type mice,
fat-1 mice subjected to pressure overload showed sustained heart
function and reduced cardiac remodeling (fibrosis) without any
difference in cardiac hypertrophy. Examination of bone marrow
transplantation revealed that enrichment of omega-3 PUFAs in
bone marrow-derived cells (mostly macrophages), but not in
cardiac cells, was responsible for the anti-fibrotic phenotype
observed in fat-1 mice subjected to pressure overload. LC–MS/MS-
based lipidomics revealed that high levels of 18-HEPE, an EPA
metabolite, were produced by fat-1 transgenic macrophages, and
18-HEPE suppressed IL-6 production from cardiac fibroblasts in
nanomolar range (Fig. 3). Of note, dietary intake of EPA ethyl ester
(2700 mg/day) significantly increased the plasma concentration of
18-HEPE. Furthermore, administration of 18-HEPE prevented
cardiac dysfunction, macrophage infiltration, and cardiac fibrosis
after transverse aortic constriction (TAC), indicating the therapeu-
tic potential of 18-HEPE for cardiac remodeling under pressure
overload [29].
Conclusions
Not all omega-3 PUFAs trials have shown reductions in CVD;
however, several adequately powered observation and inter-
vention trials have strongly supported the efficacy of omega-3
PUFAs for the prevention of CVD. Furthermore, experimental
studies have revealed multiple underlying molecular mecha-
nisms, including membrane modification, attenuation of ion
channels, regulation of pro-inflammatory gene expression,
and production of lipid mediators. It remains unclear which
mechanism contributes the most to the cardioprotective effects
of omega-3 PUFAs observed in vivo; however, the pleiotropic
anti-inflammatory effects of omega-3 PUFAs could be valuable,
especially in the setting of atherosclerosis and cardiac remodel-
ing. Although further work is needed to clarify the molecular
relationship between omega-3 PUFAs and cardiac physiology/
pathology, it might be useful to consider bioactive omega-3
PUFA-derived metabolites, such as 18-HEPE, as endogenous
anti-inflammatory molecules and potential new therapeutic
targets for CVD.
Funding
This work was supported by funding from the Japan Science and
Technology Agency Precursory Research for Embryonic Science
and Technology (PRESTO) [to M.A.], a Grant-in-aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan [to M.A.], and a Research Fellowship from
the Japan Society for the Promotion of Science for Young Scientists
[to J.E.]
Conflict of interest
The authors have no conflict of interest to disclose.
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