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Calvo et al. Omega-3 fatty acids in cardiovascular health

response. [44,45] In addition n-3 PUFAs may also prevent replacement of AA in cell membrane phospholipids,
macrophage infiltration in adipose tissue. [41] decreasing the binding rate of AA to COX-1, resulting
in reduced TXA2 synthesis, a vasoconstriction and
Thrombogenesis platelet aggregation-promoting molecule. [57] On the
The antithrombotic properties of PUFAs have been other hand, this secondarily increases the production
described since the 1980s, owing to the pioneer studies of TXA3, which exerts a significantly lower biological
by Bang and Dyerberg. [48] These studies demonstrated activity than TXA2. [58] Another mechanism observed
that the Eskimo diet, characterized by high intake with in vivo studies is the capacity of n-3 PUFAs
of seafood rich in n-3 PUFAs (mainly fish, seal and to act as TXA2 and PG H2 antagonists, through
whale), was associated with a low incidence of CVD, the synthesis of protectin DX, a product of DHA
as well as a decrease in thrombogenesis, evident by dihydroxylation obtained by the action of LOX. [59] This
high incidence of hemorrhages. [49,50] compound also has the capacity to inhibit both COX-1
and COX-2 in platelets and neutrophils, significantly
Even though these effects have been described in decreasing both platelet activation and aggregation
populations of different latitudes, [51-53] the inverse relation [Figure 3]. [60,61]
between n-3 PUFAs intake, platelet aggregation,
coagulation and fibrinolysis is still not completely In contrast, views on the mechanisms underlying
elucidated; [54] however, both in vitro and in vivo studies the anticoagulant effects of n-3 PUFAs remain
have reported that n-3 PUFAs supplementation controversial. Some studies suggest these molecules
reduces TXA2 synthesis, platelet activation and may interfere in the carboxylation of vitamin
adhesion, [55] and decreases plasminogen activator K-dependent coagulation factors II, VII, IX and X; [62,63]
inhibitor-1 (PAI-1) activity and concentration. [56] while other studies attribute more relevance to a
modification in serum fibrinogen levels. [64] Similarly,
The mechanisms by which n-3 PUFAs decrease the role of n-3 PUFAs in fibrinolysis remains unclear, [65]
thrombogenesis have been extensively studied, however it has been proposed that by unknown
especially in platelets. High n-3 PUFA intake, mechanisms, they alter PAI-1 synthesis through a
especially EPA and DHA, appears to favor the genetic pathway. [66]
Dyslipidemia
The effects of n-3 PUFAs on serum lipids were also
first ascertained by Bang and Dyerberg [67] in their
emblematic study on the Eskimo population. Results of
this study showed that individuals who stayed in their
birthplace had lower levels of triacylglycerides (TAG),
very low-density lipoproteins (VLDL-C) and low-density
lipoproteins (LDL-C), whereas those who later migrated
to Denmark showed a serum lipid profile similar to

Figure 2: Role of polyunsaturated fatty acids in proinflammatory
cytokine synthesis. EPA and DHA inhibit the production of Figure 3: Role of polyunsaturated fatty acids in thrombogenesis.
proinflammatory cytokines through different mechanisms: (1) n-3 PUFAs exert their antithrombotic effect on platelets via two
binding of EPA and DHA to the G protein-coupled receptor main processes: (1) replacement of arachidonic acid in the platelet
(GPR120) leads to its activation and binding to β arrestin-2, which membrane, which causes a decrease in the action of COX-1
then dissociates into TAB1 and inhibits TAK1, thus interrupting on arachidonic acid, diminishing TXA2 synthesis and favoring
the IKKβ/NF-κB cascade; (2) the inclusion of EPA and DHA the synthesis of TXA3; (2) activity as TXA2 antagonists through
into the lipid bilayer, which modifies lipid rafts and interrupts the the synthesis of protectin DX, a molecule from the lipoxygenase
translocation of TLR-4 and the MD2/TRIAP-MyD88/IRAK-TRAF6/ pathway, which inhibitis COX-1 and COX-2. PUFA: polyunsaturated
IKKβ/NF-κB pathway, thus inhibiting the production of cytokines, fatty acids; TXA2: thromboxane A2; TXA3: thromboxane A3; COX-
showing the antiinflammatory action of EPA and DHA 1: cyclooxygenase 1; COX-2: cyclooxygenase 2
Vessel Plus ¦ Volume 1 ¦ September 26, 2017 119