Heterogeneity of Macrophages in Atherosclerosis

Abstract

Atherosclerosis is a prevalent inflammatory condition and a frequent cause of morbidity and mortality worldwide. Macrophages are among the key immune cells driving lesion formation in the arterial wall. They have therefore evolved as potential targets for therapeutic strategies. Understanding of the different macrophage phenotypes and functions seems to be of pivotal importance for the development of treatments to target these immune cells. This review highlights the complexity of the mononuclear phagocyte system and summarizes important features of macrophage biology contributing to atherosclerosis.

Keywords

atherosclerosis - macrophage - monocyte - inflammation - therapy

• References

• 1 Global Health Estimates 2016: Deaths by Cause, Age, Sex, by Country and by Region, 2000–2016; 2018
• 2 Cole JE, Park I, Ahern DJ. , et al. Immune cell census in murine atherosclerosis: cytometry by time of flight illuminates vascular myeloid cell diversity. Cardiovasc Res 2018; 114 (10) 1360-1371
• 3 Winkels H, Ehinger E, Vassallo M. , et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ Res 2018; 122 (12) 1675-1688
• 4 Cochain C, Vafadarnejad E, Arampatzi P. , et al. Single-cell RNA-Seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ Res 2018; 122 (12) 1661-1674
• 5 Bobryshev YV, Ivanova EA, Chistiakov DA, Nikiforov NG, Orekhov AN. Macrophages and their role in atherosclerosis: pathophysiology and transcriptome analysis. BioMed Res Int 2016; 2016: 9582430
• 6 Ensan S, Li A, Besla R. , et al. Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth. Nat Immunol 2016; 17 (02) 159-168
• 7 Schulz C, Massberg S. Atherosclerosis--multiple pathways to lesional macrophages. Sci Transl Med 2014; 6 (239) 239ps2
• 8 Ginhoux F, Greter M, Leboeuf M. , et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330 (6005): 841-845
• 9 Schulz C, Gomez Perdiguero E, Chorro L. , et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 2012; 336 (6077): 86-90
• 10 Stremmel C, Schuchert R, Wagner F. , et al. Yolk sac macrophage progenitors traffic to the embryo during defined stages of development. Nat Commun 2018; 9 (01) 75
• 11 Yona S, Kim KW, Wolf Y. , et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 2013; 38 (01) 79-91
• 12 Gomez Perdiguero E, Klapproth K, Schulz C. , et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 2015; 518 (7540): 547-551
• 13 Mass E, Ballesteros I, Farlik M. , et al. Specification of tissue-resident macrophages during organogenesis. Science 2016; 353 (6304): aaf4238
• 14 Gosselin D, Link VM, Romanoski CE. , et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 2014; 159 (06) 1327-1340
• 15 Lavin Y, Winter D, Blecher-Gonen R. , et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 2014; 159 (06) 1312-1326
• 16 Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 2013; 13 (10) 709-721
• 17 Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011; 145 (03) 341-355
• 18 Lin J, Kakkar V, Lu X. Impact of MCP-1 in atherosclerosis. Curr Pharm Des 2014; 20 (28) 4580-4588
• 19 Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J, Miyata M. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A 1995; 92 (18) 8264-8268
• 20 Finney AC, Stokes KY, Pattillo CB, Orr AW. Integrin signaling in atherosclerosis. Cell Mol Life Sci 2017; 74 (12) 2263-2282
• 21 Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO, Wagner DD. The combined role of P- and E-selectins in atherosclerosis. J Clin Invest 1998; 102 (01) 145-152
• 22 Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27 (11) 2292-2301
• 23 Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL. P-selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med 2000; 191 (01) 189-194
• 24 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 2008; 117 (13) 1649-1657
• 25 Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 2010; 10 (12) 826-837
• 26 Maiellaro K, Taylor WR. The role of the adventitia in vascular inflammation. Cardiovasc Res 2007; 75 (04) 640-648
• 27 Scott NA, Cipolla GD, Ross CE. , et al. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation 1996; 93 (12) 2178-2187
• 28 Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U S A 1979; 76 (01) 333-337
• 29 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340 (02) 115-126
• 30 Randolph GJ. Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res 2014; 114 (11) 1757-1771
• 31 Shankman LS, Gomez D, Cherepanova OA. , et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 2015; 21 (06) 628-637
• 32 Feil S, Fehrenbacher B, Lukowski R. , et al. Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ Res 2014; 115 (07) 662-667
• 33 Orekhov AN, Bobryshev YV, Chistiakov DA. The complexity of cell composition of the intima of large arteries: focus on pericyte-like cells. Cardiovasc Res 2014; 103 (04) 438-451
• 34 Cybulsky MI, Iiyama K, Li H. , et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 2001; 107 (10) 1255-1262
• 35 Sundell CL, Somers PK, Meng CQ. , et al. AGI-1067: a multifunctional phenolic antioxidant, lipid modulator, anti-inflammatory and antiatherosclerotic agent. J Pharmacol Exp Ther 2003; 305 (03) 1116-1123
• 36 Tardif JC, McMurray JJ, Klug E. , et al; Aggressive Reduction of Inflammation Stops Events (ARISE) Trial Investigators. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371 (9626): 1761-1768
• 37 Besemer J, Harant H, Wang S. , et al. Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1. Nature 2005; 436 (7048): 290-293
• 38 Leuschner F, Dutta P, Gorbatov R. , et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol 2011; 29 (11) 1005-1010
• 39 Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011; 11 (11) 723-737
• 40 Chistiakov DA, Bobryshev YV, Nikiforov NG, Elizova NV, Sobenin IA, Orekhov AN. Macrophage phenotypic plasticity in atherosclerosis: the associated features and the peculiarities of the expression of inflammatory genes. Int J Cardiol 2015; 184: 436-445
• 41 Ruytinx P, Proost P, Van Damme J, Struyf S. Chemokine-induced macrophage polarization in inflammatory conditions. Front Immunol 2018; 9: 1930
• 42 Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 2014; 14 (06) 392-404
• 43 Shapouri-Moghaddam A, Mohammadian S, Vazini H. , et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 2018; 233 (09) 6425-6440
• 44 Sanson M, Distel E, Fisher EA. HDL induces the expression of the M2 macrophage markers arginase 1 and Fizz-1 in a STAT6-dependent process. PLoS One 2013; 8 (08) e74676
• 45 Turnbull IR, Gilfillan S, Cella M. , et al. Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 2006; 177 (06) 3520-3524
• 46 Kim K, Shim D, Lee JS. , et al. Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models. Circ Res 2018; 123 (10) 1127-1142
• 47 Cochain C, Zernecke A. Macrophages and immune cells in atherosclerosis: recent advances and novel concepts. Basic Res Cardiol 2015; 110 (04) 34
• 48 Al-Sharea A, Lee MK, Moore XL. , et al. Native LDL promotes differentiation of human monocytes to macrophages with an inflammatory phenotype. Thromb Haemost 2016; 115 (04) 762-772
• 49 van Tits LJ, Stienstra R, van Lent PL, Netea MG, Joosten LA, Stalenhoef AF. Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2 macrophages: a crucial role for Krüppel-like factor 2. Atherosclerosis 2011; 214 (02) 345-349
• 50 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 (06) 737-746
• 51 Finn AV, Nakano M, Polavarapu R. , et al. Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J Am Coll Cardiol 2012; 59 (02) 166-177
• 52 Boyle JJ, Harrington HA, Piper E. , et al. Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol 2009; 174 (03) 1097-1108
• 53 Habib A, Finn AV. The role of iron metabolism as a mediator of macrophage inflammation and lipid handling in atherosclerosis. Front Pharmacol 2014; 5: 195
• 54 Boyle JJ. Heme and haemoglobin direct macrophage Mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage. Curr Opin Lipidol 2012; 23 (05) 453-461
• 55 Gleissner CA, Shaked I, Little KM, Ley K. CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages. J Immunol 2010; 184 (09) 4810-4818
• 56 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 2015; 21 (03) 255-265
• 57 Erbel C, Wolf A, Lasitschka F. , et al. Prevalence of M4 macrophages within human coronary atherosclerotic plaques is associated with features of plaque instability. Int J Cardiol 2015; 186: 219-225
• 58 Murray PJ, Allen JE, Biswas SK. , et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 2014; 41 (01) 14-20
• 59 De Paoli F, Staels B, Chinetti-Gbaguidi G. Macrophage phenotypes and their modulation in atherosclerosis. Circ J 2014; 78 (08) 1775-1781
• 60 Schmidt SV, Krebs W, Ulas T. , et al. The transcriptional regulator network of human inflammatory macrophages is defined by open chromatin. Cell Res 2016; 26 (02) 151-170
• 61 Hilgendorf I, Swirski FK, Robbins CS. Monocyte fate in atherosclerosis. Arterioscler Thromb Vasc Biol 2015; 35 (02) 272-279
• 62 Colin S, Chinetti-Gbaguidi G, Staels B. Macrophage phenotypes in atherosclerosis. Immunol Rev 2014; 262 (01) 153-166
• 63 Lim HY, Lim SY, Tan CK. , et al. Hyaluronan receptor LYVE-1-expressing macrophages maintain arterial tone through hyaluronan-mediated regulation of smooth muscle cell collagen. Immunity 2018; 49 (06) 1191
• 64 Kubota Y, Takubo K, Shimizu T. , et al. M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med 2009; 206 (05) 1089-1102
• 65 Hume DA, MacDonald KP. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood 2012; 119 (08) 1810-1820
• 66 Buck MD, Sowell RT, Kaech SM, Pearce EL. Metabolic instruction of immunity. Cell 2017; 169 (04) 570-586
• 67 O'Neill LA, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med 2016; 213 (01) 15-23
• 68 Wang F, Zhang S, Jeon R. , et al. Interferon gamma induces reversible metabolic reprogramming of M1 macrophages to sustain cell viability and pro-inflammatory activity. EBioMedicine 2018; 30: 303-316
• 69 Artyomov MN, Sergushichev A, Schilling JD. Integrating immunometabolism and macrophage diversity. Semin Immunol 2016; 28 (05) 417-424
• 70 Divakaruni AS, Hsieh WY, Minarrieta L. , et al. Etomoxir inhibits macrophage polarization by disrupting CoA homeostasis. Cell Metab 2018; 28 (03) 490-503
• 71 Ross R, Glomset JA. Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 1973; 180 (4093): 1332-1339
• 72 Goldstein JL, Brown MS. The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem 1977; 46: 897-930
• 73 Gimbrone Jr MA. Endothelial dysfunction, hemodynamic forces, and atherosclerosis. Thromb Haemost 1999; 82 (02) 722-726
• 74 Borén J, Olin K, Lee I, Chait A, Wight TN, Innerarity TL. Identification of the principal proteoglycan-binding site in LDL. A single-point mutation in apo-B100 severely affects proteoglycan interaction without affecting LDL receptor binding. J Clin Invest 1998; 101 (12) 2658-2664
• 75 Adamson S, Leitinger N. Phenotypic modulation of macrophages in response to plaque lipids. Curr Opin Lipidol 2011; 22 (05) 335-342
• 76 Yoshida H, Kisugi R. Mechanisms of LDL oxidation. Clin Chim Acta 2010; 411 (23-24): 1875-1882
• 77 Cyrus T, Witztum JL, Rader DJ. , et al. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest 1999; 103 (11) 1597-1604
• 78 Shih DM, Xia YR, Wang XP. , et al. Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem 2000; 275 (23) 17527-17535
• 79 Hegele RA. Paraoxonase genes and disease. Ann Med 1999; 31 (03) 217-224
• 80 Lee MK, Moore XL, Fu Y. , et al. High-density lipoprotein inhibits human M1 macrophage polarization through redistribution of caveolin-1. Br J Pharmacol 2016; 173 (04) 741-751
• 81 van der Vorst EPC, Theodorou K, Wu Y. , et al. High-density lipoproteins exert pro-inflammatory effects on macrophages via passive cholesterol depletion and PKC-NF-κB/STAT1-IRF1 signaling. Cell Metab 2017; 25 (01) 197-207
• 82 Podrez EA, Febbraio M, Sheibani N. , et al. Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J Clin Invest 2000; 105 (08) 1095-1108
• 83 Suzuki H, Kurihara Y, Takeya M. , et al. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature 1997; 386 (6622): 292-296
• 84 Stewart CR, Stuart LM, Wilkinson K. , et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010; 11 (02) 155-161
• 85 Febbraio M, Podrez EA, Smith JD. , et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest 2000; 105 (08) 1049-1056
• 86 Yakubenko VP, Bhattacharjee A, Pluskota E, Cathcart MK. αMβ₂ integrin activation prevents alternative activation of human and murine macrophages and impedes foam cell formation. Circ Res 2011; 108 (05) 544-554
• 87 Xu XH, Shah PK, Faure E. , et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation 2001; 104 (25) 3103-3108
• 88 Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 2007; 13 (11) 460-469
• 89 Yvan-Charvet L, Wang N, Tall AR. Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler Thromb Vasc Biol 2010; 30 (02) 139-143
• 90 Maguire EM, Pearce SWA, Xiao Q. Foam cell formation: a new target for fighting atherosclerosis and cardiovascular disease. Vascul Pharmacol 2019; 112: 54-71
• 91 Fazio S, Babaev VR, Murray AB. , et al. Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages. Proc Natl Acad Sci U S A 1997; 94 (09) 4647-4652
• 92 Lee SD, Tontonoz P. Liver X receptors at the intersection of lipid metabolism and atherogenesis. Atherosclerosis 2015; 242 (01) 29-36
• 93 Kappus MS, Murphy AJ, Abramowicz S. , et al. Activation of liver X receptor decreases atherosclerosis in Ldlr⁻/⁻ mice in the absence of ATP-binding cassette transporters A1 and G1 in myeloid cells. Arterioscler Thromb Vasc Biol 2014; 34 (02) 279-284
• 94 Singh R, Kaushik S, Wang Y. , et al. Autophagy regulates lipid metabolism. Nature 2009; 458 (7242): 1131-1135
• 95 Razani B, Feng C, Coleman T. , et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab 2012; 15 (04) 534-544
• 96 Jiang Y, Wang M, Huang K. , et al. Oxidized low-density lipoprotein induces secretion of interleukin-1β by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation. Biochem Biophys Res Commun 2012; 425 (02) 121-126
• 97 de Torre-Minguela C, Mesa Del Castillo P, Pelegrín P. The NLRP3 and pyrin inflammasomes: implications in the pathophysiology of autoinflammatory diseases. Front Immunol 2017; 8: 43
• 98 Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 2010; 7 (02) 77-86
• 99 Duewell P, Kono H, Rayner KJ. , et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464 (7293): 1357-1361
• 100 Dragoljevic D, Kraakman MJ, Nagareddy PR. , et al. Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis. Eur Heart J 2018; 39 (23) 2158-2167
• 101 Nagareddy PR, Kraakman M, Masters SL. , et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab 2014; 19 (05) 821-835
• 102 Murphy AJ, Dragoljevic D, Tall AR. Cholesterol efflux pathways regulate myelopoiesis: a potential link to altered macrophage function in atherosclerosis. Front Immunol 2014; 5: 490
• 103 Lee MKS, Al-Sharea A, Dragoljevic D, Murphy AJ. Hand of FATe: lipid metabolism in hematopoietic stem cells. Curr Opin Lipidol 2018; 29 (03) 240-245
• 104 Krieger M. The other side of scavenger receptors: pattern recognition for host defense. Curr Opin Lipidol 1997; 8 (05) 275-280
• 105 Mäkinen PI, Lappalainen JP, Heinonen SE. , et al. Silencing of either SR-A or CD36 reduces atherosclerosis in hyperlipidaemic mice and reveals reciprocal upregulation of these receptors. Cardiovasc Res 2010; 88 (03) 530-538
• 106 de Winther MP, Gijbels MJ, van Dijk KW. , et al. Scavenger receptor deficiency leads to more complex atherosclerotic lesions in APOE3Leiden transgenic mice. Atherosclerosis 1999; 144 (02) 315-321
• 107 Moore KJ, Kunjathoor VV, Koehn SL. , et al. Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice. J Clin Invest 2005; 115 (08) 2192-2201
• 108 Mehta JL, Sanada N, Hu CP. , et al. Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. Circ Res 2007; 100 (11) 1634-1642
• 109 Xu S, Ogura S, Chen J, Little PJ, Moss J, Liu P. LOX-1 in atherosclerosis: biological functions and pharmacological modifiers. Cell Mol Life Sci 2013; 70 (16) 2859-2872
• 110 Dove DE, Su YR, Swift LL, Linton MF, Fazio S. ACAT1 deficiency increases cholesterol synthesis in mouse peritoneal macrophages. Atherosclerosis 2006; 186 (02) 267-274
• 111 Fazio S, Major AS, Swift LL. , et al. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. J Clin Invest 2001; 107 (02) 163-171
• 112 Yang L, Yang JB, Chen J. , et al. Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone. Cell Res 2004; 14 (04) 315-323
• 113 Hoffmann PR, deCathelineau AM, Ogden CA. , et al. Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J Cell Biol 2001; 155 (04) 649-659
• 114 Ravichandran KS, Lorenz U. Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol 2007; 7 (12) 964-974
• 115 Tabas I. Apoptosis and plaque destabilization in atherosclerosis: the role of macrophage apoptosis induced by cholesterol. Cell Death Differ 2004; 11 (Suppl. 01) S12-S16
• 116 Liao X, Sluimer JC, Wang Y. , et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab 2012; 15 (04) 545-553
• 117 Schrijvers DM, De Meyer GR, Kockx MM, Herman AG, Martinet W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25 (06) 1256-1261
• 118 Seimon T, Tabas I. Mechanisms and consequences of macrophage apoptosis in atherosclerosis. J Lipid Res 2009; 50 (Suppl): S382-S387
• 119 Elliott MR, Chekeni FB, Trampont PC. , et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 2009; 461 (7261): 282-286
• 120 Szondy Z, Garabuczi E, Joós G, Tsay GJ, Sarang Z. Impaired clearance of apoptotic cells in chronic inflammatory diseases: therapeutic implications. Front Immunol 2014; 5: 354
• 121 Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007; 81 (01) 1-5
• 122 Mao Y, Finnemann SC. Regulation of phagocytosis by Rho GTPases. Small GTPases 2015; 6 (02) 89-99
• 123 Tajbakhsh A, Rezaee M, Kovanen PT, Sahebkar A. Efferocytosis in atherosclerotic lesions: malfunctioning regulatory pathways and control mechanisms. Pharmacol Ther 2018; 188: 12-25
• 124 Ait-Oufella H, Kinugawa K, Zoll J. , et al. Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice. Circulation 2007; 115 (16) 2168-2177
• 125 Thorp E, Cui D, Schrijvers DM, Kuriakose G, Tabas I. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice. Arterioscler Thromb Vasc Biol 2008; 28 (08) 1421-1428
• 126 Tao H, Yancey PG, Babaev VR. , et al. Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. J Lipid Res 2015; 56 (08) 1449-1460
• 127 Cai B, Thorp EB, Doran AC. , et al. MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 2017; 127 (02) 564-568
• 128 Ait-Oufella H, Pouresmail V, Simon T. , et al. Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis. Arterioscler Thromb Vasc Biol 2008; 28 (08) 1429-1431
• 129 Wan E, Yeap XY, Dehn S. , et al. Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction. Circ Res 2013; 113 (08) 1004-1012
• 130 Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339 (19) 1349-1357
• 131 Libby P, Pasterkamp G, Crea F, Jang IK. Reassessing the mechanisms of acute coronary syndromes. Circ Res 2019; 124 (01) 150-160
• 132 Ridker PM, Everett BM, Thuren T. , et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 (12) 1119-1131
• 133 Ridker PM, Cannon CP, Morrow D. , et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352 (01) 20-28
• 134 Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012; 380 (9841): 565-571
• 135 Bohula EA, Giugliano RP, Cannon CP. , et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation 2015; 132 (13) 1224-1233
• 136 Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013; 61 (04) 404-410
• 137 Ridker PM, Everett BM, Pradhan A. , et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019; 380 (08) 752-762
• 138 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 2013; 166 (02) 199-207