Stability of Unsaturated Methyl Esters of Fatty Acids on Surfaces
Mechanism underlying the cardioprotective effects of omega-3 poly unsaturated fatty acids
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Transcript of Mechanism underlying the cardioprotective effects of omega-3 poly unsaturated fatty acids
Omega-3 poly unsaturated fatty acids
Flaxseed, canola, walnut,
soybean oil, seeweed, kidney
beans
Sea food: anchovy, herring, salmon,mackerel,bluefish, sardin,
trout,tilefish,swordfish,tu
na
Predominantyby
endogenous metabolism rather than
diet
Omega3 response
to inflammation
Indirect
Antithrombotic and
antiinflammatory
effect
Inflammation
resolving
Direct Regulation of
transcription factor
Suppresion of APRs
Change in memberane lipid
composition
Inhibiting expression of
chemokines, VCAM, ICAM, NF-KP
activation,nuetrophilmigration
Lower macrophage-produced cytokines including IL-1α ,IL-
1β, TNFα,MCP1
Inhibition of neutrophil
transmigration and infiltration
Reduceneutrophil recruiment
Adkins etal.2010
Family Drived form Main effect
Lipoxins Arachidonic Acid (AA), especially inpresence of omega-3 EPA and DHAfrom 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 endingacute inflammation; synthesis of Protectinsbegins immediatelyafter acute injury.
Serhan CN. 2008
APRs Acute-phase reactants are proteins whose concentrations increaseor decrease by 25% during injury or inflammatory states.
C3 component of complements, haptoglobin,ferritin, α-1 antitrypsin, albumin, transferrin, apolipoprotein CIII (ApoCIII), CRP, fibrinogen and SAA.
NF-κB As a major transcription factor in inflammatory responses,nuclear factor B (NF-B) is involved in the regulation ofinflammatory and immune genes, apoptosis and cell proliferation.
NF-B is the general name for a family of transcriptionfactors consisting of 5 members: p65 (RelA), c-Rel, RelB,NF-B1 (p50 and its precursor p105), and NF-B2 (p52 andits precursor p100).
Toll-like receptor 4(TLR4) a key receptor in the development of atherosclerosisToll-like receptor 4 generates downstream signaling cascadesthat lead to NF-κBactivation and expression of COX-2, inflammatorycytokines 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,
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 indicatesubiquitination.
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
Lipid rafts Caveolae Signal transduction
endocytosisoncogenesisUptake 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
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
Decreasing endothelial activation
Endothelial cells ICAM-1VCAM-1E-selectinP-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
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
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
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
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