Cytokines: Roles in atherosclerosis disease progression and potential therapeutic targets

Future Medicinal Chemistry

Volumn 8, Issue 11, 2016, Pages 1317-1330

  Moss, Joe W E ^a   Ramji, Dipak P ^a  

^a CARDIFF UNIVERSITY   (United Kingdom)

Author keywords

atherosclerosis; cardiovascular disease; chemokines; cytokines; foam cells; inflammation; nanoparticles; neutralization

Indexed keywords

CARDIOVASCULAR AGENT; CYTOKINE;

ATHEROSCLEROSIS; ATHEROSCLEROTIC PLAQUE; DISEASE COURSE; DRUG TARGETING; HUMAN; INFLAMMATION; META ANALYSIS (TOPIC); MONOCYTE; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN STABILITY; REVIEW; CARDIOVASCULAR DISEASES; METABOLISM; PATHOLOGY;

ATHEROSCLEROSIS; CARDIOVASCULAR DISEASES; CYTOKINES; DISEASE PROGRESSION; HUMANS; INFLAMMATION;

EID: 84982893584     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc-2016-0072     Document Type: Review

References (110)

1. WHO. World Health Organization Fact Sheet 317 (2015). www. who. int/mediacentre/factsheets/fs317/en/
2. Mozaffarian D, Benjamin EJ, Go AS et al. Heart disease and stroke statistics-2015 update: A report from the American Heart Association. Circulation 131(4), e29-e322 (2015).
3. Ait-Oufella H, Taleb S, Mallat Z, Tedgui A. Recent advances on the role of cytokines in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31(5), 969-979 (2011).
4. Buckley ML, Ramji DP. The influence of dysfunctional signaling and lipid homeostasis in mediating the inflammatory responses during atherosclerosis. Biochim. Biophys. Acta Mol. Basis Dis. 1852(7), 1498-1510 (2015).
5. McLaren JE, Michael DR, Ashlin TG, Ramji DP. Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. Prog. Lipid Res. 50(4), 331-347 (2011).
6. Ramji DP, Davies TS. Cytokines in atherosclerosis: key players in all stages of disease and promising therapeutic targets. Cytokine Growth Factor Rev. 26(6), 673-685 (2015).
7. Moss JWE, Ramji DP. Interferon-?: promising therapeutic target in atherosclerosis. World J. Exp. Med. 5(3), 154-159 (2015).
8. Boshuizen MCS, de Winther MPJ. Interferons as essential modulators of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 35(7), 1579-1588 (2015).
9. Chinetti-Gbaguidi G, Colin S, Staels B. Macrophage subsets in atherosclerosis. Nat. Rev. Cardiol. 12(1), 10-17 (2015).
10. Wolfs IMJ, Donners MMPC, de Winther MPJ. Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation. Thromb. Haemost. 106(5), 763-771 (2011).
11. Leitinger N, Schulman IG. Phenotypic polarization of macrophages in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 33(6), 1120-1126 (2013).
12. Kzhyshkowska J, Neyen C, Gordon S. Role of macrophage scavenger receptors in atherosclerosis. Immunobiology 217, 492-502 (2012).
13. Canton J, Neculai D, Grinstein S. Scavenger receptors in homeostasis and immunity. Nat. Rev. Immunol. 13, 621-634 (2013).
14. Andres V, Pello OM, Silvestre-Roig C. Macrophage proliferation and apoptosis in atherosclerosis. Curr. Opin. Lipidol. 23(5), 429-438 (2012).
15. Ohman MK, Wright AP, Wickenheiser KJ, Luo W, Russo HM, Eitzman DT. Monocyte chemoattractant protein-1 deficiency protects against visceral fat-induced atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 30(6), 1151-1158 (2010).
16. Yadav A, Saini V, Arora S. MCP-1: chemoattractant with a role beyond immunity: A review. Clin. Chim. Acta 411(21-22), 1570-1579 (2010).
17. Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci. Signal. 3(105), cm1 (2010).
18. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117(14), 3720-3732 (2011).
19. Van Tassell BW, Toldo S, Mezzaroma E, Abbate A. Targeting interleukin-1 in heart disease. Circulation 128(17), 1910-1923 (2013).
20. Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ. Res. 118(1), 145-156 (2016).
21. Liu W, Yin Y, Zhou Z, He M, Dai Y. OxLDL-induced IL-1 beta secretion promoting foam cells formation was mainly via CD36 mediated ROS production leading to NLRP3 inflammasome activation. Inflamm. Res. 63(1), 33-43 (2014).
22. Akhurst RJ, Hata A. Targeting the TGF? signalling pathway in disease. Nat. Rev. Drug Discov. 11(10), 790-811 (2012).
23. Reifenberg K, Cheng F, Orning C et al. Overexpression of TGF-?1 in macrophages reduces and stabilizes atherosclerotic plaques in ApoE-deficient mice. PLoS ONE 7(7), e40990 (2012).
24. Lievens D, Habets KL, Robertson A-K et al. Abrogated transforming growth factor beta receptor II (TGF?RII) signalling in dendritic cells promotes immune reactivity of T cells resulting in enhanced atherosclerosis. Eur. Heart J. 34(48), 3717-3727 (2013).
25. Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity 39(6), 1003-1018 (2013).
26. McLaren JE, Michael DR, Salter RC et al. IL-33 reduces macrophage foam cell formation. J. Immunol. 185, 1222-1229 (2010).
27. Kakkar R, Lee RT. The IL-33/ST2 pathway: Therapeutic target and novel biomarker. Nat. Rev. Drug Discov. 7(10), 827-840 (2008).
28. Ali S, Mohs A, Thomas M et al. The dual function cytokine IL-33 interacts with the transcription factor NF-?B to dampen NF-?B-stimulated gene transcription. J. Immunol. 187(4), 1609-1616 (2011).
29. Miller AM, Xu D, Asquith DL et al. IL-33 reduces the development of atherosclerosis. J. Exp. Med. 205(2), 339-346 (2008).
30. Moore K, Sheedy F, Fisher E. Macrophages in atherosclerosis: A dynamic balance. Nat. Rev. Immunol. 13, 709-721 (2013).
31. Soehnlein O, Drechsler M, Döring Y et al. Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes. EMBO Mol. Med. 5(3), 471-481 (2013).
32. Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat. Rev. Cardiol. 7(2), 77-86 (2010).
33. Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17(11), 1410-1422 (2011).
34. Koenen RR, Weber C. Therapeutic targeting of chemokine interactions in atherosclerosis. Nat. Rev. Drug Discov. 9(2), 141-153 (2010).
35. Zernecke A, Weber C. Chemokines in atherosclerosis: proceedings resumed. Arterioscler. Thromb. Vasc. Biol. 34(4), 742-750 (2014).
36. Ingersoll MA, Platt AM, Potteaux S, Randolph GJ. Monocyte trafficking in acute and chronic inflammation. Trends Immunol. 32(10), 470-477 (2011).
37. Zernecke A, Weber C. Chemokines in the vascular inflammatory response of atherosclerosis. Cardiovasc. Res. 86(2), 192-201 (2010).
38. Combadière C, Potteaux S, Rodero M et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 117(13), 1649-1657 (2008).
39. Liu XL, Zhang PF, Ding SF et al. Local gene silencing of monocyte chemoattractant protein-1 prevents vulnerable plaque disruption in apolipoprotein E-knockout mice. PLoS ONE 7(3), e33497 (2012).
40. Wong HS, Jaumouillé V, Freeman SA et al. Chemokine signaling enhances CD36 responsiveness toward oxidized low-density lipoproteins and accelerates foam cell formation. Cell Rep. 14(12), 2859-2871 (2016).
41. Colin S, Chinetti-Gbaguidi G, Staels B. Macrophage phenotypes in atherosclerosis. Immunol. Rev. 262(1), 153-166 (2014).
42. Erbel C, Tyka M, Helmes CM et al. CXCL4-induced plaque macrophages can be specifically identified by co-expression of MMP7+S100A8+ in vitro and in vivo. Innate Immun. 21(3), 255-265 (2015).
43. Zhang K, Huang X, Li X et al. Interleukin 6 destabilizes atherosclerotic plaques by downregulating prolyl-4-hydroxylase ?1 via a mitogen-activated protein kinase and c-Jun pathway. Arch. Biochem. Biophys. 528(2), 127-133 (2012).
44. Han X, Kitamoto S, Wang H, Boisvert WA. Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice. FASEB J. 24(8), 2869-2880 (2010).
45. Oh J, Riek AE, Weng S et al. Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J. Biol. Chem. 287(15), 11629-11641 (2012).
46. Xiao N, Yin M, Zhang L et al. Tumor necrosis factor-alpha deficiency retards early fatty-streak lesion by influencing the expression of inflammatory factors in apoE-null mice. Mol. Genet. Metab. 96(4), 239-244 (2009).
47. Xanthoulea S, Thelen M, Pöttgens C, Gijbels MJJ, Lutgens E, de Winther MPJ. Absence of p55 TNF receptor reduces atherosclerosis, but has no major effect on angiotensin II induced aneurysms in LDL receptor deficient mice. PLoS ONE 4(7), e6113 (2009).
48. Kamari Y, Shaish A, Shemesh S et al. Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1?. Biochem. Biophys. Res. Commun. 405(2), 197-203 (2011).
49. Shemesh S, Kamari Y, Shaish A et al. Interleukin-1 receptor type-1 in non-hematopoietic cells is the target for the proatherogenic effects of interleukin-1 in apoE-deficient mice. Atherosclerosis 222(2), 329-336 (2012).
50. Bhat OM, Kumar PU, Giridharan NV, Kaul D, Kumar MJM, Dhawan V. Interleukin-18-induced atherosclerosis involves CD36 and NF-?B crosstalk in Apo E-/-mice. J. Cardiol. 66(1), 28-35 (2015).
51. Pejnovic N, Vratimos A, Lee SH et al. Increased atherosclerotic lesions and Th17 in interleukin-18 deficient apolipoprotein E-knockout mice fed high-fat diet. Mol. Immunol. 47(1), 37-45 (2009).
52. Schuett H, Oestreich R, Waetzig GH et al. Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 32(2), 281-290 (2012).
53. van Es T, van Puijvelde GHM, Michon IN et al. IL-15 aggravates atherosclerotic lesion development in LDL receptor deficient mice. Vaccine 29(5), 976-983 (2011).
54. Sastre C, Fernández-Laso V, Madrigal-Matute J et al. Genetic deletion or TWEAK blocking antibody administration reduce atherosclerosis and enhance plaque stability in mice. J. Cell. Mol. Med. 18(4), 721-734 (2014).
55. McLaren JE, Calder CJ, McSharry BP et al. The TNF-like protein 1A-death receptor 3 pathway promotes macrophage foam cell formation in vitro. J. Immunol. 184(10), 5827-5834 (2010).
56. Gistera A, Robertson AK, Andersson J et al. Transforming growth factor-beta signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17 dependent pathway. Atherosclerosis 235(2), e88-e89 (2014).
57. Reifenberg K, Cheng F, Twardowski L et al. T cell-specific overexpression of TGFb1 fails to influence atherosclerosis in APOE-deficient mice. PLoS ONE 8(12), e81444 (2013).
58. Michael DR, Salter RC, Ramji DP. TGF-? inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: A dominant role for Smad-2. Biochim. Biophys. Acta 1822(10), 1608-1616 (2012).
59. Cardilo-Reis L, Gruber S, Schreier SM et al. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol. Med. 4(10), 1072-1086 (2012).
60. Siasos G, Tousoulis D, Kioufis S et al. Inflammatory mechanisms in atherosclerosis: The impact of matrix metalloproteinases. Curr. Top. Med. Chem. 12(10), 1132-1148 (2012).
61. Koga M, Kai H, Yasukawa H et al. Inhibition of progression and stabilization of plaques by postnatal interferon-gamma function blocking in ApoE-knockout mice. Circ Res. 101(4), 348-356 (2007).
62. Alexander MR, Moehle CW, Johnson JL et al. Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. J. Clin. Invest. 122(1), 70-79 (2012).
63. Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr. Pharm. Des. 18(11), 1519-1530 (2012).
64. Parker BA, Capizzi JA, Grimaldi AS et al. Effect of statins on skeletal muscle function. Circulation 127(1), 96-103 (2013).
65. Ridker PM, Danielson E, Fonseca FAH et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med. 359(21), 2195-2207 (2008).
66. NHS. Statins-side effects (2016). www. nhs. uk/Conditions/Cholesterol-lowering-
67. Ridker PM, Howard CP, Walter V et al. Effects of interleukin-1? inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: A Phase IIb randomized, placebo-controlled trial. Circulation. 126(23), 2739-2748 (2012).
68. Koenig W. High-sensitivity C-reactive protein and atherosclerotic disease: from improved risk prediction to riskguided therapy. Int. J. Cardiol. 168(6), 5126-5134 (2013).
69. Everett BM, Pradhan AD, Solomon DH et al. Rationale and design of the Cardiovascular Inflammation Reduction Trial: A test of the inflammatory hypothesis of atherothrombosis. Am. Heart J. 166(2), 199-207. e15 (2013).
70. Li N, McLaren JE, Michael DR, Clement M, Fielding CA, Ramji DP. ERK is integral to the IFN-gamma-mediated activation of STAT1, the expression of key genes implicated in atherosclerosis, and the uptake of modified lipoproteins by human macrophages. J. Immunol. 185, 3041-3048 (2010).
71. Lee H, Chung H, Lee H, Jeong L, Lee S. Suppression of inflammation response by a novel A3 adenosine receptor agonist thio-Cl-IB-MECA through inhibition of Akt and NF-?B signaling. Immunobiology 216, 997-1003 (2011).
72. Voloshyna I, Hai O, Littlefield M, Carsons S, Reiss A. Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via PPAR? and adenosine. Eur. J. Pharmacol. 698, 299-309 (2013).
73. White GE, Iqbal AJ, Greaves DR. CC chemokine receptors and chronic inflammation-therapeutic opportunities and pharmacological challenges. Pharmacol. Rev. 65(1), 47-89 (2013).
74. Bursill CA, McNeill E, Wang L et al. Lentiviral gene transfer to reduce atherosclerosis progression by long-term CCchemokine inhibition. Gene Ther. 16(1), 93-102 (2009).
75. Nie P, Li D, Hu L et al. Atorvastatin improves plaque stability in ApoE-knockout mice by regulating chemokines and chemokine receptors. PLoS ONE 9(5), e97009 (2014).
76. Majmudar MD, Keliher EJ, Heidt T et al. Monocytedirected RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice. Circulation 127(20), 2038-2046 (2013).
77. Olzinski AR, Turner GH, Bernard RE et al. Pharmacological inhibition of C-C chemokine receptor decreases macrophage infiltration in the aortic root of the human C-C chemokine receptor 2/apolipoproteinE-/-mouse: Magnetic resonance imaging assessment. Arterioscler. Thromb. Vasc. Biol. 30(2), 253-259 (2010).
78. Gilbert J, Lekstrom-Himes J, Donaldson D et al. Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region. Am. J. Cardiol. 107(6), 906-911 (2011).
79. Cipriani S, Francisci D, Mencarelli A et al. Efficacy of the CCR5 antagonist maraviroc in reducing early, ritonavirinduced atherogenesis and advanced plaque progression in mice. Circulation 127(21), 2114-2124 (2013).
80. Chain B, Arnold J, Akthar S et al. A linear epitope in the n-terminal domain of CCR5 and its interaction with antibody. PLoS ONE 10(6), e0128381 (2015).
81. Poupel L, Boissonnas A, Hermand P et al. Pharmacological inhibition of the chemokine receptor, CX3CR1, reduces atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 33(10), 2297-2305 (2013).
82. Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 32, 659-702 (2014).
83. Striz I, Brabcova E, Kolesar L, Sekerkova A. Cytokine networking of innate immunity cells: A potential target of therapy. Clin. Sci. (Lond). 126(9), 593-612 (2014).
84. Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16(4), 343-353 (2015).
85. Christian DA, Hunter CA. Particle-mediated delivery of cytokines for immunotherapy. Immunotherapy 4(4), 425-441 (2012).
86. Chacko A-M, Hood ED, Zern BJ, Muzykantov VR. Targeted nanocarriers for imaging and therapy of vascular inflammation. Curr. Opin. Colloid Interface Sci. 16(3), 215-227 (2011).
87. Jayagopal A, Linton MF, Fazio S, Haselton FR. Insights into atherosclerosis using nanotechnology. Curr. Atheroscler. Rep. 12(3), 209-215 (2010).
88. Lewis DR, Kamisoglu K, York AW, Moghe PV. Polymerbased therapeutics: nanoassemblies and nanoparticles for management of atherosclerosis. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 3(4), 400-420 (2011).
89. Chung EJ. Targeting and therapeutic peptides in nanomedicine for atherosclerosis. Exp. Biol. Med. (Maywood) (2016).
90. Almer G, Summers KL, Scheicher B et al. Interleukin 10-coated nanoparticle systems compared for molecular imaging of atherosclerotic lesions. Int. J. Nanomed. 9, 4211-4222 (2014).
91. Fredman G, Kamaly N, Spolitu S et al. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci. Transl. Med. 7(275), 275ra20 (2015).
92. Slavin JL, Lloyd B. Health benefits of fruits and vegetables. Adv. Nutr. An Int. Rev. J. 3(4), 506-516 (2012).
93. Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: The anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr. Rev. 68(5), 280-289 (2010).
94. Granados-Principal S, Quiles JL, Ramirez-Tortosa CL, Sanchez-Rovira P, Ramirez-Tortosa MC. Hydroxytyrosol: from laboratory investigations to future clinical trials. Nutr. Rev. 68(4), 191-206 (2010).
95. 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. 32(9), 2122-2130 (2012).
96. Song Y, Zhang LJ, Li H et al. Polyunsaturated fatty acid relatively decreases cholesterol content in THP-1 macrophage-derived foam cell: partly correlates with expression profile of CIDE and PAT members. Lipids Heal. Dis. 12(1), 111 (2013).
97. McLaren JE, Michael DR, Guschina IA, Harwood JL, Ramji DP. Eicosapentaenoic acid and docosahexaenoic acid regulate modified LDL uptake and macropinocytosis in human macrophages. Lipids 46(11), 1053-1061 (2011).
98. Niki T, Wakatsuki T, Yamaguchi K et al. Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound. Circ. J. 80(2), 450-460 (2016).
99. Franzese CJ, Bliden KP, Gesheff MG et al. Relation of fish oil supplementation to markers of atherothrombotic risk in patients with cardiovascular disease not receiving lipidlowering therapy. Am. J. Cardiol. 115(9), 1204-1211 (2015).
100. 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. 31(9), 1963-1972 (2011).
101. Calder PC. Mechanisms of action of (n-3) fatty acids. J. Nutr. 142(3), S592-S599 (2012).
102. Enns JE, Yeganeh A, Zarychanski R et al. The impact of omega-3 polyunsaturated fatty acid supplementation on the incidence of cardiovascular events and complications in peripheral arterial disease: A systematic review and metaanalysis. BMC Cardiovasc. Disord. 14(1), 70 (2014).
103. Kwak S, Myung S, Lee Y, Seo H. Korean Meta-analysis Study Group f. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: A metaanalysis of randomized, double-blind, placebo-controlled trials. Arch. Intern. Med. 172(9), 686-694 (2012).
104. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: A systematic review and meta-analysis. JAMA 308(10), 1024-1033 (2012).
105. Morrison M, van der Heijden R, Heeringa P et al. Epicatechin attenuates atherosclerosis and exerts antiinflammatory effects on diet-induced human-CRP and NF?B in vivo. Atherosclerosis 233(1), 149-156 (2014).
106. Sansone R, Rodriguez-Mateos A, Heuel J et al. Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: A randomised, controlled, double-masked trial: The Flaviola Health Study. Br. J. Nutr. 114(8), 1246-1255 (2015).
107. Sabeva NS, McPhaul CM, Li X, Cory TJ, Feola DJ, Graf GA. Phytosterols differentially influence ABC transporter expression, cholesterol efflux and inflammatory cytokine secretion in macrophage foam cells. J. Nutr. Biochem. 22(8), 777-783 (2011).
108. Rosignoli P, Fuccelli R, Fabiani R, Servili M, Morozzi G. Effect of olive oil phenols on the production of inflammatory mediators in freshly isolated human monocytes. J. Nutr. Biochem. 24(8), 1513-1519 (2013).
109. Fito M, Cladellas M, de la Torre R et al. Anti-inflammatory effect of virgin olive oil in stable coronary disease patients: A randomized, crossover, controlled trial. Eur. J. Clin. Nutr. 62(4), 570-574 (2008).
110. Moss JWE, Davies TS, Garaiova I, Plummer SF, Michael DR, Ramji DP. A unique combination of nutritionally active ingredients can prevent several key processes associated with atherosclerosis in vitro. PLoS ONE 11(3), e0151057 (2016).