Mechanism underlying the cardioprotective effects of omega-3 poly unsaturated fatty acids

2. Parisa Zarei Shargh
Asie Ahmadi Hoseini
Fariba Mohajer
Mashhad University Of Medical Science

3. Omega-3 poly unsaturated fatty acids
Flaxseed,
canola, walnut,
soybean oil,
seeweed, kidney
beans
Sea food:
anchovy, herring,
salmon,mackerel
,bluefish, sardin,
trout,tile
fish,swordfish,tu
na
Predominanty
by
endogenous
metabolism
rather than
diet

4. 0.2%
-
8%
0%
-
4%

5. Yang etal.2009

6. Omega3 response
to inflammation
Indirect
Antithrombotic and
antiinflammatory
effect
Inflammation
resolving
Direct
Regulation of
transcription factor
Suppresion of
APRs
Change in
memberane lipid
composition

7. Mechanism of Omega3 PUFA
on cardiovascular health

8. Caterina R.NEJM.2011
Hydro-peroxy
ecosatetra
enoic acid
Epoxy
ecosatrionic
acid

9. Inhibiting
expression of
chemokines, VCAM,
ICAM, NF-KP
activation,nuetrophil
migration
Lower macrophage-
produced cytokines
including IL-1α ,IL-
1β, TNFα,MCP1
Inhibition of
neutrophil
transmigration
and infiltration
Reduceneutrop
hil recruiment
Adkins etal.2010

10. Family Drived form Main effect
Lipoxins Arachidonic Acid (AA),
especially in
presence of omega-3
EPA and DHA
from fish oil
Potent triggers that
end acute
inflammation
Resolvins Omega-3 EPA and
DHA from fish oil
Novel Anti-
Inflammatory and
Inflammation
Resolving Mediators
Protectins Omega-3 DHA from
fish oil
Especially active in
protecting brain tissue
by promptly ending
acute inflammation;
synthesis of Protectins
begins immediately
after acute injury.
Serhan CN. 2008

11. APRs Acute-phase reactants
are proteins whose
concentrations increase
or decrease by 25%
during injury or
inflammatory states.
C3 component of
complements,
haptoglobin,
ferritin, α-1 antitrypsin,
albumin, transferrin,
apolipoprotein CIII (Apo
CIII), CRP, fibrinogen and
SAA.
NF-κB As a major transcription
factor in inflammatory
responses,nuclear factor
B (NF-B) is involved in the
regulation of
inflammatory and
immune genes,
apoptosis and cell
proliferation.
NF-B is the general name
for a family of
transcription
factors consisting of 5
members: p65 (RelA), c-
Rel, RelB,
NF-B1 (p50 and its
precursor p105), and NF-
B2 (p52 and
its precursor p100).

12. Toll-like receptor 4(TLR4) a key receptor in the
development of
atherosclerosis
Toll-like receptor 4
generates downstream
signaling cascades
that lead to NF-κB
activation and expression
of COX-2, inflammatory
cytokines and adhesion
molecules.
Peroxisome proliferator-
activated receptors)
PPAR(
have also been shown to
affect the NF-B signaling
pathway. PPARα has
strong anti-inflammatory
properties.
PPARα, PPARγ and PPARδ,

13. Menno P.J .2005
NF-B activation. Two NF-B activation
cascades can be discriminated.
The classical NF-B activation pathway
(left) involves the activation of the IKK
complex with the subsequent
degradation of IB and nuclear
translocation of the NF-B dimer.
The alternative NF-B activation cascade
(right) is mediated through IKK1 and
results in the processing of p100 to
p52, resulting in the nuclear transfer
of the relB-p52 dimer. Ub indicates
ubiquitination.

14. Mozaffarian, D J2011

15.  w-3 PUFA prevents CVD by changing properties of cell
membrane….
 Alters the content of the membrane PL FA.
 Alter microdomain lipid composition
 Membrane effects on ion channel conductance
Yuriko Akins et al.2010

16.  Lipid rafts Caveolae
 Signal transduction
endocytosis
oncogenesis
Uptake of pathogenic bacteria & certain
viruses
 When n-3 PUFA is introduced, the
microdomain lipid composition is altered: the
sphingomyelin content in lipid rafts and the
cholesterol and caveolin in caveolae are
reduced .
Yuriko Akins et
al.2010

17. W-3 PUFAs prevents arrhythmias through multiple mechanisms :
1.Mechanismis that n-3 PUFA reduced membrane electrical
excitability and activity of voltage-dependent Na+ channels in
cardiomyocytes.
This is mediated through an increase in the threshold of depolarizing
current required to initiate an action potential and by prolonging the
refractory period following an action potential.
2. By cytosolic free Ca2+ variability exhibited a modulatory action on L-
type Ca2+ channels, which resulted in lowered cytosolic free Ca2+ and
Ca2+ influx rate however,
AA led to Ca2+ overload during a period of ischemic stress .
Yuriko Akins et al.2010

18. Decreasing endothelial activation

Endothelial cells ICAM-1
VCAM-1
E-selectin
P-selectin
Are involved in leukocyte recruitment and platelet adhesion during
thrombosis and inflammation and also contribute to early phases
of atherogenesis .
 PUFA have been shown to inhibit the production of inflammatory
cytokines that activate the endothelium .
 N-3 PUFA Decreasing the expression of adhesion molecule in
human monocytes and murine macrophages.
Yuriko Akins et al.2010

19. Vasorelaxant effect of DHA
 The vasorelaxant effect of DHA has been attributed to
the decreases in Ca2+ influx in VSMCs .
 N-3 PUFA can modify eicosanoid production to favor
vasodilation and antithrombotic actions.
 N-3 PUFAs increase endothelium-dependent
relaxation through an enhancement of NO release.
NO inhibits platelet aggregation and adhesion,
leukocyte adhesion and smooth muscle cell proliferation
.
Logan Bronwell.2012

20.  Exaggerated VSMC growth results in arterial damage and is an
important component in the pathogenesis of atherosclerosis.
 DHA to a lesser extent, can affect vascular function through the
inhibition in VSMC growth and proliferation at various steps of the
signal transduction pathway of growth factors .
Darshan S. Kwlley and Yuriko Adkins.2012

21.  Elevated fasting and postprandial plasma TG levels increase
inflammation and are independent risk factors for CVD.
 DHA supplementation reduced both the fasting and
postprandial TGs by more than 25% hypertriglyceridemic men
.
 DHA also decreased the concentrations of atherogenic small
dense LDL particles, total LDL particles and the remnant
chylomicron particles.
 Decrease Apo CIII , SREBP-1c activity ,FA substrates for
lipogenesis
 Increase LPL ,FXR ,PPARα-induced oxidation ,Apo CII ,VLDL-
receptor gene expression
Darshan S. Kelley et al .2009

22. Dariush Mozaffarian .2011

23. Arrhythmia
Decrease Two-series PG
Surface membrane electrical excitability :
Activity of voltage-dependent Na+ channels
Ca2+ release channels and intracellular Ca2+
Increase Three-series PG
Stimulation Proresolving mediators
Increase Lipoxins, resolvins and protectins
Stabilization of atherosclerotic plaques
Decrease Infiltration of monocytes into the plaques
Activity of cells, that is, macrophages within the plaques
Increase Incorporation of n-3 PUFA into plaques
TG & cholesterol lowering
Decrease Apo CIII , SREBP-1c activity ,FA substrates for lipogenesis
Increase LPL ,FXR ,PPARα-induced oxidation ,Apo CII ,VLDL-receptor gene
expression
Changes in membrane lipid composition
Decrease Sphingomyelin content in lipid rafts
Cholesterol and caveolin in caveolae
Increase Membrane fluidity
Result