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Clinical features - Review

EPA’s pleiotropic mechanisms of action: a narrative review

ORCID Icon, , , ORCID Icon, , & show all
Pages 651-664 | Received 04 Mar 2021, Accepted 21 Apr 2021, Published online: 13 May 2021

Figures & data

Figure 1. Cellular and Molecular Mechanisms of Atherosclerosis and the Role of EPA

Adapted with permission from Atherosclerosis, 242(1), Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis, 357–366, copyright 2015, with permission from Elsevier [Citation37]. ACAT = acyl CoA:cholesterol acyltransferase; Apo E = apolipoprotein E; CCR = C-C chemokine receptor; CD = clusters of differentiation; CS = connecting segment; EPA = eicosapentaenoic acid; EPA/AA = eicosapentaenoic acid/arachidonic acid ratio; HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive protein; ICAM = intercellular adhesion molecule; IFN = interferon; IL = interleukin; iNOS = inducible nitric oxide synthase; LDL = low-density lipoprotein; LO = lipoxygenase; Lp-PLA2 = lipoprotein-associated phospholipase A2; MCP = monocyte chemotactic protein; mm-LDL = minimally modified LDL; MMP = matrix metalloproteinase; ox-LDL = oxidized LDL; RLP-C = remnant-like lipoparticle cholesterol; SMC = smooth muscle cell; Th = T helper; VCAM = vascular cell adhesion molecule.
Figure 1. Cellular and Molecular Mechanisms of Atherosclerosis and the Role of EPA

Table 1. Effect of EPA on Lipid Markers, Inflammatory Markers, and Atherosclerotic Plaque

Figure 2. Bioactive Metabolites of EPA

EPA is metabolized by COX and LOX enzymes to form anti-inflammatory mediators (resolvins) as well as an anti-aggregatory and vasodilatory mediator (PGI3). Pro-aggregatory (TXA3) and pro-inflammatory mediators (PGE3 and LTB5) derived from EPA are weak. COX = cyclooxygenase; EPA = eicosapentaenoic acid; HEPE = hydroxyeicosapentaenoic acid; HPEPE = hydroperoxyeicosapentaenoic acid; LOX = lipoxygenase; LT = leukotriene; PG = prostaglandin; Rv = resolvin; TX = thromboxane.
Figure 2. Bioactive Metabolites of EPA

Table 2. EPA-Derived Bioactive Metabolites That Control Inflammation and Tissue Homeostasis

Figure 3. Proposed Molecular Mechanisms of Cardioprotection by Omega-3 Fatty Acids

Adapted with permission from J Cardiol, 67, Endo J, Arita M. Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. J Cardiol, 22–27, copyright 2016, with permission from Elsevier [Citation51]. Ca = calcium; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; FA = fatty acid; GPCR(GPR120) = G protein-coupled receptor 120; Na = sodium; NFκB = nuclear factor-κB; NLRP3 = NOD-like receptor family, pyrin domain containing 3; PLA2 = phospholipase A2; PPARs = peroxisome proliferator-activated receptors; TGF-β = transforming growth factor-β.
Figure 3. Proposed Molecular Mechanisms of Cardioprotection by Omega-3 Fatty Acids

Figure 4. Lipid Interactions of EPA and Impact on Vascular Health

Schematic illustration of the proposed location of phospholipid-linked EPA in cellular membranes and lipoproteins. EPA is rapidly esterified and incorporated into lipoproteins and membrane phospholipids. Biophysical studies indicate EPA has an extended orientation that preserves membrane fluidity as well as inhibition of lipid oxidation and membrane cholesterol domain formation. Reproduced with permission from O’Connell et al. [Citation112], Attribution-NonCommercial 4.0 International (CC BY-NC 4.0; https://creativecommons.org/licenses/by-nc/4.0/). ApoB = apolipoprotein B; EPA = eicosapentaenoic acid; IPE = icosapent ethyl; LDL = low-density lipoprotein cholesterol.
Figure 4. Lipid Interactions of EPA and Impact on Vascular Health

Figure 5. Icosapent Ethyl Effects on RLP-C From the MARINE and ANCHOR Studies

Reproduced with permission from Ballantyne et al. [Citation40], Attribution-NonCommercial-NoDerivatives 4.0International (CC BY-NC-ND 4.0; https://creativecommons.org/licenses/by-nc-nd/4.0/). RLP-C = remnant-like particle cholesterol.
Figure 5. Icosapent Ethyl Effects on RLP-C From the MARINE and ANCHOR Studies