Omega-3 fatty acids: Mechanisms underlying 'protective effects' in atherosclerosis

Current Opinion in Lipidology

Volumn 24, Issue 4, 2013, Pages 345-350

  Chang, Chuchun L ^a   Deckelbaum, Richard J ^a  

^a Columbia University ^*  (United States)

Author keywords

Atherosclerosis; Inflammation; Lipoprotein lipase; Macrophages; N 3 fatty acids

Indexed keywords

DOCOSAHEXAENOIC ACID; ICOSAPENTAENOIC ACID; LIPOPROTEIN LIPASE; OMEGA 3 FATTY ACID;

ANTIINFLAMMATORY ACTIVITY; ARTERY WALL; ATHEROGENESIS; ATHEROSCLEROSIS; CARDIOVASCULAR RISK; CYTOKINE PRODUCTION; DRUG MECHANISM; HEART ATRIUM FIBRILLATION; HEART PROTECTION; INFLAMMATION; LEUKOCYTE; LIPID STORAGE; MACROPHAGE; MONOCYTE; PERIPHERAL OCCLUSIVE ARTERY DISEASE; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ATHEROSCLEROSIS; CARDIOTONIC AGENTS; DIET; FATTY ACIDS, OMEGA-3; HUMANS; LIPID METABOLISM; LIPOPROTEIN LIPASE; PLAQUE, ATHEROSCLEROTIC;

EID: 84880578189     PISSN: 09579672     EISSN: 14736535     Source Type: Journal    
DOI: 10.1097/MOL.0b013e3283616364     Document Type: Review

References (76)

1. Hoyert DL. 75 years of mortality in the United States, 1935-2010 NCHS data brief, no.88. Hyattsville, MD: National Center for Health Statistics; 2012.
2. Micha R, Mozaffarian D. Saturated fat and cardiometabolic risk factors, coronary heart disease, stroke, and diabetes: a fresh look at the evidence. Lipids 2010; 45:893-905.
3. Wang C, Harris WS, Chung M, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 2006; 84:5-17.
4. Harris WS. Are n-3 fatty acids still cardioprotective? Curr Opin Clin Nutr Metab Care 2013; 16:141-149.
5. Rizos EC, Ntzani EE, Bika E, et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA 2012; 308:1024-1033.
6. Adkins Y, Kelley DS. Mechanisms underlying the cardioprotective effects of omega-3 polyunsaturated fatty acids. J Nutr Biochem 2010; 21:781-792.
7. Jung UJ, Torrejon C, Tighe AP, Deckelbaum RJ. n-3 Fatty acids and cardiovascular disease: mechanisms underlying beneficial effects. Am J Clin Nutr 2008; 87:2003S-2009S.
8. De Caterina R. n-3 fatty acids in cardiovascular disease. N Engl J Med 2011; 364:2439-2450.
9. Sudheendran S, Chang CC, Deckelbaum RJ. N-3 vs. saturated fatty acids: effects on the arterial wall. Prostaglandins Leukot Essent Fatty Acids 2010; 82:205-209.
10. Calder PC. Mechanisms of action of (n-3) fatty acids. J Nutr 2012; 142:592S-599S.
11. Chen W, Jump DB, Esselman WJ, Busik JV. Inhibition of cytokine signaling in human retinal endothelial cells through modification of caveolae/lipid rafts by docosahexaenoic acid. Invest Ophthalmol Vis Sci 2007; 48:18-26.
12. Massaro M, Basta G, Lazzerini G, et al. Quenching of intracellular ROS generation as a mechanism for oleate-induced reduction of endothelial activation and early atherogenesis. Thromb Haemost 2002; 88:335-344.
13. Oh DY, Talukdar S, Bae EJ, et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010; 142:687-698.
14. Nair SS, Leitch JW, Falconer J, Garg ML. Prevention of cardiac arrhythmia by dietary (n-3) polyunsaturated fatty acids and their mechanism of action. J Nutr 1997; 127:383-393.
15. von Schacky C. Omega-3 fatty acids and cardiovascular disease. Curr Opin Clin Nutr Metab Care 2004; 7:131-136.
16. Kowey PR, Reiffel JA, Ellenbogen KA, et al. Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA 2010; 304:2363-2372.
17. Kumar S, Sutherland F, Morton JB, et al. Long-term omega-3 polyunsaturated fatty acid supplementation reduces the recurrence of persistent atrial fibrillation after electrical cardioversion. Heart Rhythm 2012; 9:483-491.
18. Wu JH, Lemaitre RN, King IB, et al. Association of plasma phospholipid longchain omega-3 fatty acids with incident atrial fibrillation in older adults: the cardiovascular health study. Circulation 2012; 125:1084-1093.
19. Buckley CD, Gilroy DW, Serhan CN, et al. The resolution of inflammation. Nat Rev Immunol 2012; 13:59-66.
20. Gajos G, Zalewski J, Rostoff P, et al. Reduced thrombin formation and altered fibrin clot properties induced by polyunsaturated omega-3 fatty acids on top of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (OMEGA-PCI clot). Arterioscler Thromb Vasc Biol 2011; 31:1696-1702.
21. Calder PC. The role of marine omega-3 (n-3) fatty acids in inflammatory processes, atherosclerosis and plaque stability. Mol Nutr Food Res 2012; 56:1073-1080.
22. Moertl D, Berger R, Hammer A, et al. Dose-dependent decrease of platelet activation and tissue factor by omega-3 polyunsaturated fatty acids in patients with advanced chronic heart failure. Thromb Haemost 2011; 106:457-465.
23. Mackay I, Ford I, Thies F, et al. Effect of omega-3 fatty acid supplementation on markers of platelet and endothelial function in patients with peripheral arterial disease. Atherosclerosis 2012; 221:514-520.
24. Thies F, Garry JM, Yaqoob P, et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 2003; 361:477-485.
25. Cawood AL, Ding R, Napper FL, et al. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis 2010; 212:252-259.
26. Matsumoto M, Sata M, Fukuda D, et al. Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice. Atherosclerosis 2008; 197:524-533.
27. Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circulation research 1992; 71:850-858.
28. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007; 116:1832-1844.
29. Botham KM, Bravo E, Elliott J, Wheeler-Jones CP. Direct interaction of dietary lipids carried in chylomicron remnants with cells of the artery wall: implications for atherosclerosis development. Curr Pharm Des 2005; 11:3681-3695.
30. De Pascale C, Avella M, Perona JS, et al. Fatty acid composition of chylomicron remnant-like particles influences their uptake and induction of lipid accumulation in macrophages. FEBS J 2006; 273:5632-5640.
31. Seo T, Qi K, Chang C, et al. Saturated fat-rich diet enhances selective uptake of LDL cholesteryl esters in the arterial wall. J Clin Invest 2005; 115:2214-2222.
32. Chang CL, Seo T, Matsuzaki M, et al. n-3 fatty acids reduce arterial LDLcholesterol delivery and arterial lipoprotein lipase levels and lipase distribution. Arterioscler Thromb Vasc Biol 2009; 29:555-561.
33. Chang CL, Seo T, Du CB, et al. n-3 Fatty acids decrease arterial low-density lipoprotein cholesterol delivery and lipoprotein lipase levels in insulin-resistant mice. Arterioscler Thromb Vasc Biol 2010; 30:2510-2517.
34. Yagyu H, Chen G, Yokoyama M, et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest 2003; 111:419-426.
35. Merkel M, Heeren J, Dudeck W, et al. Inactive lipoprotein lipase (LPL) alone increases selective cholesterol ester uptake in vivo, whereas in the presence of active LPL it also increases triglyceride hydrolysis and whole particle lipoprotein uptake. J Biol Chem 2002; 277:7405-7411.
36. Torrejon C, Jung U, Deckelbaum R, Uauy R. n-3 fatty acids as part of a saturated fatty acid rich diet reduces plasma lipids levels, and arterial inflammatory markers in LDLR KO mice [abstract]. FASEB J 2011; 25:339.8.
37. Miles EA, Banerjee T, Calder PC. The influence of different combinations of gamma-linolenic, stearidonic and eicosapentaenoic acids on the fatty acid composition of blood lipids and mononuclear cells in human volunteers. Prostaglandins Leukot Essent Fatty Acids 2004; 70:529-538.
38. Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17:1410-1422.
39. Rader DJ, Pure E. Lipoproteins, macrophage function, and atherosclerosis: beyond the foam cell? Cell Metab 2005; 1:223-230.
40. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003; 19:71-82.
41. Swirski FK, Libby P, Aikawa E, et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007; 117:195-205.
42. Tacke F, Alvarez D, Kaplan TJ, et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 2007; 117:185-194.
43. Brown AL, Zhu X, Rong S, et al. Omega-3 fatty acids ameliorate atherosclerosis by favorably altering monocyte subsets and limiting monocyte recruitment to aortic lesions. Arterioscler Thromb Vasc Biol 2012; 32:2122-2130.
44. Grenon SM, Aguado-Zuniga J, Hatton JP, et al. Effects of fatty acids on endothelial cells: inflammation and monocyte adhesion. J Surg Res 2012; 177:e35-e43.
45. Luu NT, Madden J, Calder PC, et al. Dietary supplementation with fish oil modifies the ability of human monocytes to induce an inflammatory response. J Nutr 2007; 137:2769-2774.
46. Jung UJ, Torrejon C, Chang CL, et al. Fatty acids regulate endothelial lipase and inflammatory markers in macrophages and in mouse aorta: a role for PPARgamma. Arterioscler Thromb Vasc Biol 2012; 32:2929-2937.
47. Li L, Beauchamp MC, Renier G. Peroxisome proliferator-activated receptor alpha and gamma agonists upregulate human macrophage lipoprotein lipase expression. Atherosclerosis 2002; 165:101-110.
48. Hayek T, Hussein K, Aviram M, et al. Macrophage foam-cell formation in streptozotocin-induced diabetic mice: stimulatory effect of glucose. Atherosclerosis 2005; 183:25-33.
49. Lee JY, Sohn KH, Rhee SH, Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 2001; 276:16683-16689.
50. Lee JY, Zhao L, Youn HS, et al. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem 2004; 279:16971-16979.
51. Lee JY, Plakidas A, Lee WH, et al. Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res 2003; 44:479-486.
52. Wong SW, Kwon MJ, Choi AM, et al. Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J Biol Chem 2009; 284:27384-27392.
53. Maloney E, Sweet IR, Hockenbery DM, et al. Activation of NF-kappaB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation. Arterioscler ThrombVasc Biol 2009; 29:1370-1375.
54. Lassegue B, Griendling KK. NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb Vasc Biol 2010; 30:653-661.
55. Johnson JL, Newby AC. Macrophage heterogeneity in atherosclerotic plaques. Curr Opin Lipidol 2009; 20:370-378.
56. Hansson GK, Libby P. The immune response in atherosclerosis: a doubleedged sword. Nat Rev Immunol 2006; 6:508-519.
57. Shapiro H, Lutaty A, Ariel A. Macrophages, meta-inflammation, and immunometabolism. Scientific World Journal 2011; 11:2509-2529.
58. Kadl A, Meher AK, Sharma PR, et al. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ Res 2010; 107:737-746.
59. Serhan CN, Yang R, Martinod K, et al. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J Exp Med 2009; 206:15-23.
60. Merched AJ, Ko K, Gotlinger KH, et al. Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J 2008; 22:3595-3606.
61. Serhan CN, Clish CB, Brannon J, et al. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med 2000; 192:1197-1204.
62. Szanto A, Balint BL, Nagy ZS, et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPARgamma-regulated gene expression in macrophages and dendritic cells. Immunity 2010; 33:699-712.
63. Villanueva CJ, Waki H, Godio C, et al. TLE3 is a dual-function transcriptional coregulator of adipogenesis. Cell Metab 2011; 13:413-427.
64. Vats D, Mukundan L, Odegaard JI, et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 2006; 4:13-24.
65. Rotzius P, Thams S, Soehnlein O, et al. Distinct infiltration of neutrophils in lesion shoulders in ApoE-/- mice. Am J Pathol 2010; 177:493-500.
66. Drechsler M, Megens RT, van Zandvoort M, et al. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 2010;122:1837-1845.
67. Doring Y, Drechsler M, Wantha S, et al. Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ Res 2012; 110:1052-1056.
68. Healy DA, Wallace FA, Miles EA, et al. Effect of low-to-moderate amounts of dietary fish oil on neutrophil lipid composition and function. Lipids 2000; 35:763-768.
69. Tull SP, Yates CM, Maskrey BH, et al. Omega-3 Fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment. PLoS Biol 2009; 7:e1000177.
70. Draper E, Reynolds CM, Canavan M, et al. Omega-3 fatty acids attenuate dendritic cell function via NF-kappaB independent of PPARgamma. J Nutr Biochem 2011; 22:784-790.
71. Kong W, Yen JH, Vassiliou E, et al. Docosahexaenoic acid prevents dendritic cell maturation and in vitro and in vivo expression of the IL-12 cytokine family. Lipids Health Dis 2010; 9:12.
72. Kong W, Yen JH, Ganea D. Docosahexaenoic acid prevents dendritic cell maturation, inhibits antigen-specific Th1/Th17 differentiation and suppresses experimental autoimmune encephalomyelitis. Brain Behav Immun 2011; 25:872-882.
73. Wang H, Hao Q, Li QR, et al. Omega-3 polyunsaturated fatty acids affect lipopolysaccharide-induced maturation of dendritic cells through mitogenactivated protein kinases p38. Nutrition 2007; 23:474-482.
74. Nakajima K, Yamashita T, Kita T, et al. Orally administered eicosapentaenoic acid induces rapid regression of atherosclerosis via modulating the phenotype of dendritic cells in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 2011; 31:1963-1972.
75. Vassiliou EK, Kesler OM, Tadros JH, Ganea D. Bone marrow-derived dendritic cells generated in the presence of resolvin E1 induce apoptosis of activated CD4+ T cells. J Immunol 2008; 181:4534-4544.
76. Libby P, Okamoto Y, Rocha VZ, Folco E. Inflammation in atherosclerosis: transition from theory to practice. Circ J 2010; 74:213-220.