Diversity of Denizens of the Atherosclerotic Plaque

Abstract

HomeCirculationVol. 117, No. 25Diversity of Denizens of the Atherosclerotic Plaque Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDiversity of Denizens of the Atherosclerotic PlaqueNot All Monocytes Are Created Equal Peter Libby, MD, Matthias Nahrendorf, MD, PhD, Mikael J. Pittet, PhD and Filip K. Swirski, PhD Peter LibbyPeter Libby From the Donald W. Reynolds Cardiovascular Clinical Research Center, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (P.L., F.K.S.); Center for Systems Biology, Massachusetts General Hospital, and Harvard Medical School, Boston, Mass (M.N., M.J.P.); and Center for Molecular Imaging Research, Massachusetts General Hospital, and Harvard Medical School, Charlestown, Mass (M.N., M.J.P., F.K.S.). Search for more papers by this author , Matthias NahrendorfMatthias Nahrendorf From the Donald W. Reynolds Cardiovascular Clinical Research Center, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (P.L., F.K.S.); Center for Systems Biology, Massachusetts General Hospital, and Harvard Medical School, Boston, Mass (M.N., M.J.P.); and Center for Molecular Imaging Research, Massachusetts General Hospital, and Harvard Medical School, Charlestown, Mass (M.N., M.J.P., F.K.S.). Search for more papers by this author , Mikael J. PittetMikael J. Pittet From the Donald W. Reynolds Cardiovascular Clinical Research Center, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (P.L., F.K.S.); Center for Systems Biology, Massachusetts General Hospital, and Harvard Medical School, Boston, Mass (M.N., M.J.P.); and Center for Molecular Imaging Research, Massachusetts General Hospital, and Harvard Medical School, Charlestown, Mass (M.N., M.J.P., F.K.S.). Search for more papers by this author and Filip K. SwirskiFilip K. Swirski From the Donald W. Reynolds Cardiovascular Clinical Research Center, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (P.L., F.K.S.); Center for Systems Biology, Massachusetts General Hospital, and Harvard Medical School, Boston, Mass (M.N., M.J.P.); and Center for Molecular Imaging Research, Massachusetts General Hospital, and Harvard Medical School, Charlestown, Mass (M.N., M.J.P., F.K.S.). Search for more papers by this author Originally published24 Jun 2008https://doi.org/10.1161/CIRCULATIONAHA.108.783068Circulation. 2008;117:3168–3170The atherosclerotic plaque typically harbors cells of several lineages whose conversations, mediated by extracellular or cell surface–associated messengers, influence decisively the biology and clinical consequences of the lesion. Early vascular biology studies defined the resting state of the endothelium, characterized by the elaboration of antithrombotic and vasodilatory mediators. The activated endothelium recruits inflammatory leukocytes, favors clot accumulation, participates in angiogenesis, and can influence the behavior of subjacent smooth muscle cells in ways that favor atherogenesis and vasoconstriction (Figure). More recently, we have come to appreciate that the endothelial cell not only can exhibit a spectrum of functions, but that some may arise postnatally from bone marrow–derived precursors.1 Thus, the heterogeneity of endothelial cells depends not only on the mutability of their function but also on their origin. The diversity of endothelium depends not only on lineage but also location, with increasingly well-understood differences between arterial, microvascular, and venous endothelial cells. Download figureDownload PowerPointFigure. Heterogeneity of major cell types in atherosclerotic plaques. Vascular biologists have long recognized heterogeneity of endothelial cells and smooth muscle cells, now understood to result from local mediator milieu, biomechanical stimuli, and different embryological origins. Indeed, recent data suggest that both of these intrinsic vascular cell types can arise in postnatal life from bone marrow–derived precursors. Immunological dogma recognizes several T-cell populations, exemplified here by the Th1 and Th2 subsets, which on the balance exert opposing influences on atherogenesis. New data now establish the relevance to atherosclerosis and hyperlipidemia of monocyte heterogeneity. Monocytes that bear high levels of the markers Ly6c/Gr-1 and P-selectin glycoprotein ligand exhibit more proinflammatory functions than their counterparts, which have lower levels of these surface markers. These novel observations illustrate the complexity of the inflammatory response in atherosclerosis, provide new pathophysiological insight into lesion biology, and may even afford therapeutic opportunity based on selective targeting of these subsets of inflammatory cells.Article p 3227Smooth muscle cells also exhibit diversity (Figure). Phenotypic modulation of smooth muscle cells, from those rich in contractile elements and quiescent to those that acquire more fibroblastoid features such as heightened extracellular matrix synthesis, migration, and proliferation, characterizes atherogenesis.2 Smooth muscle cells that invest the walls of different arteries derive from distinct germ layers and embryonic precursors. As in the case of endothelial cells, smooth muscle cells in arterial hyperplastic lesions such as atheromata can also arise from bone marrow precursors.3,4Activated endothelial cells recruit leukocytes to nascent atheromata. Among the leukocytic cell types captured by the endothelium, we have detailed knowledge of the T lymphocyte, now known to exert important regulatory influences on the other cells that congregate in the lesions. The functional diversity of T-cell subtypes influences many chronic inflammatory diseases, atherosclerosis included (Figure). Th1 cells and their signature mediators drive atherothrombosis. Products of Th2 cells can mitigate inflammation and may mute atherogenesis.5 Regulatory T cells may have a special role in promoting plaque rupture and thrombosis.6Mononuclear phagocytes by far outnumber T lymphocytes in the typical atheroma. These foot soldiers of the inflammatory response appear to follow commands issued from the less-abundant lymphocytes. Hints on diversity in macrophages that populate atheromata have surfaced over the years. Only a subpopulation of macrophages appears to express the potent procoagulant tissue factor, a common trigger of arterial thrombosis.7 Likewise, a pool of polymorph-like macrophages in plaques contains myeloperoxidase and “neutrophil” elastase.8,9 We long ago described selectivity in gene expression in lesional macrophages.10 Whether functional subpopulations of macrophages arise from differential stimuli encountered in regions of the plaque (eg, from T cells) or might reflect lineal predispositions that depend on programming before penetration into the plaque has remained an open question. Recent work has begun to shed new light on this unresolved aspect of the inflammatory pathways that critically influence plaque biology.In 2007, 2 groups simultaneously and independently reported that hypercholesterolemic mice exhibit a profound shift in their populations of peripheral blood monocytes, as defined by a surface marker of as-yet-uncertain functional significance known as Ly-6C or 6r-1 (Figure).11,12 The normocholesterolemic mouse has approximately equal numbers of circulating monocytes bearing low or high levels of this marker (Ly6Clo and Ly6Chi subsets). After consumption of an atherogenic diet, the Ly6Chi population rises exponentially. In mice that lack apolipoprotein E and hence have susceptibility to diet-induced hyperlipidemia and atherosclerosis, cells bearing high levels of Ly-6C accumulate in plaques preferentially. Multiple mechanisms seem to promote the prominence of Ly6Chi cells in peripheral blood and plaques. Many indications point to cells of the Ly6Chi subset as particularly proinflammatory (Table).13 Notably, the Ly-6Chi cells contain higher levels of myeloperoxidase, certain proteinases, and proinflammatory cytokines such as tumor necrosis factor α.14 Emerging data in the mouse show important and divergent functional roles for the Ly-6Clo and Ly-6Chi subsets in other conditions such as the healing of myocardial infarction and visceral adiposity.14Table. Monocyte Subsets Preferentially Express Certain Effector FunctionsProteolysisPhagocytosisInflammationOxidationAngiogenesisLy-6chi++++−Ly-6clo−+−−+The application of these concepts to human disease has lagged, in part because of the lack of consensus on the human correlates of the subsets conveniently defined in mice by the Ly-6C marker. Human monocytes do not express Ly-6C or an evident homolog, leaving the field a bit unsettled about how to translate the exciting results in mice to our human patients.13,15,16,17 In the current issue of Circulation, An et al provide data that promise to help us out of this translational quandary and, more fundamentally, furnish new functional insight into how the inflammatory subset of blood monocytes may selectively accumulate at sites of endothelial activation and thrombosis.18 These workers provide evidence that the P-selectin glycoprotein ligands track with Ly-6C in mouse mononuclear phagocytes, and very importantly lend support to the notion that the CD16− population of mononuclear cells represents a proinflammatory population of monocytes in humans. Activated endothelial cells elevate expression of the leukocyte adhesion molecule P-selectin. Elegant work by Denisa Wagner and her colleagues has defined a role for P-selectin in leukocyte recruitment to sites of inflammation and in experimental atherogenesis.19,20 Platelets, once activated, exteriorize preformed P-selectin, increasing their adhesivity to activated endothelium and probably promoting the stability and propagation of thrombi. Thus, P-selectin on endothelial cells may recruit selectively the inflammatory subset of mononuclear phagocytes to sites of early atherogenesis, and P-selectin exteriorized and released locally by activated platelets may recruit and retain particularly proinflammatory populations of monocytes at sites of thrombosis. The activated platelet also exteriorizes and releases locally the potent macrophage agonist CD40 ligand (CD154), previously shown by us to promote progression of experimental atheroma and to induce tissue factor production by monocyte/macrophages.21,22,23,24 In this manner, P-selectin glycoprotein ligands/P-selectin interaction may provide a multipronged phlogistic stimulus that amplifies local inflammation and tightens the lasso that links inflammation and thrombosis.25The more we learn, the more we appreciate the importance of heterogeneity of cells in the plaque. Monocytes have now joined their brethren in the atheroma as deriving from precursors of diverse origin as well as acquiring different function palettes in response to local signals. The work of the Oklahoma group reported here represents a major boost to our understanding of the functions of the recently identified proinflammatory pool of mononuclear phagocytes. Moreover, their discovery provides us with a powerful tool to probe the role of this cell population in the pathogenesis of human diseases. The recognition of this heterogeneity in the phagocytes in plaques also points to strategies that target selectively the recruitment or maturation of the proinflammatory subset as a new avenue for the therapy of atherosclerosis and its complications.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Sources of FundingThis work was supported by grants from the Donald W. Reynolds Foundation (Dr Libby) and the National Institutes of Health (HL-34636 to Dr Libby).DisclosuresNone.FootnotesCorrespondence to Peter Libby, MD, 77 Ave Louis Pasteur, NRB7, Boston, MA 02115. E-mail: [email protected] References 1 Werner N, Nickenig G. Endothelial progenitor cells in health and atherosclerotic disease. Ann Med. 2007; 39: 82–90.CrossrefMedlineGoogle Scholar2 Mahoney WM, Schwartz SM. Defining smooth muscle cells and smooth muscle injury. J Clin Invest. 2005; 115: 221–224.CrossrefMedlineGoogle Scholar3 Saiura A, Sata M, Hirata Y, Nagai R, Makuuchi M. Circulating smooth muscle progenitor cells contribute to atherosclerosis. Nat Med. 2001; 7: 382–383.CrossrefMedlineGoogle Scholar4 Shimizu K, Sugiyama S, Aikawa M, Fukumoto Y, Rabkin E, Libby P, Mitchell RN. Host bone-marrow cells are a source of donor intimal smooth-muscle-like cells in murine aortic transplant arteriopathy. Nat Med. 2001; 7: 738–741.CrossrefMedlineGoogle Scholar5 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6: 508–519.CrossrefMedlineGoogle Scholar6 Robertson AK, Rudling M, Zhou X, Gorelik L, Flavell RA, Hansson GK. Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest. 2003; 112: 1342–1350.CrossrefMedlineGoogle Scholar7 Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A. 1989; 86: 2839–2843.CrossrefMedlineGoogle Scholar8 Sugiyama S, Okada Y, Sukhova GK, Virmani R, Heinecke JW, Libby P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Path. 2001; 158: 879–891.CrossrefMedlineGoogle Scholar9 Dollery CM, Owen CA, Sukhova GK, Krettek A, Shapiro SD, Libby P. Neutrophil elastase in human atherosclerotic plaques: production by macrophages. Circulation. 2003; 107: 2829–2836.LinkGoogle Scholar10 Salomon RN, Underwood R, Doyle MV, Wang A, Libby P. Increased apolipoprotein E and c-fms gene expression without elevated interleukin 1 or 6 levels indicate selective activation of macrophage functions in advanced human atheroma. Proc Natl Acad Sci U S A. 1992; 89: 2814–2818.CrossrefMedlineGoogle Scholar11 Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ. Ly-6C monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrphages in atheromata. J Clin Invest. 2007; 117: 195–205.CrossrefMedlineGoogle Scholar12 Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007; 117: 185–194.CrossrefMedlineGoogle Scholar13 Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003; 19: 71–82.CrossrefMedlineGoogle Scholar14 Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007; 204: 3037–3047.CrossrefMedlineGoogle Scholar15 Gordon S. Macrophage heterogeneity and tissue lipids. J Clin Invest. 2007; 117: 89–93.CrossrefMedlineGoogle Scholar16 Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005; 5: 953–964.CrossrefMedlineGoogle Scholar17 Waldo SW, Li Y, Buono C, Zhao B, Billings EM, Chang J, Kruth HS. Heterogeneity of human macrophages in culture and in atherosclerotic plaques. Am J Path. 2008; 172: 1112–1126.CrossrefMedlineGoogle Scholar18 An G, Wang H, Tang R, Yago T, McDaniel JM, McGee S, Huo Y. Xia L. P-Selectin glycoprotein ligand-1 is highly expressed on Ly-6Chi monocytes and a major determinant for Ly-6Chi monocyte recruitment to sites of atherosclerosis in mice. Circulation. 2008; 117: 3227–3237.LinkGoogle Scholar19 Johnson RC, Chapman SM, Dong ZM, Ordovas JM, Mayadas TN, Herz J, Hynes RO, Schaefer EJ, Wagner DD. Absence of P-selectin delays fatty streak formation in mice. J Clin Invest. 1997; 99: 1037–1043.CrossrefMedlineGoogle Scholar20 Dong ZM, Brown AA, Wagner DD. Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice. Circulation. 2000; 101: 2290–2295.CrossrefMedlineGoogle Scholar21 Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998; 391: 591–594.CrossrefMedlineGoogle Scholar22 Mach F, Schoenbeck U, Bonnefoy J-Y, Pober JS, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation. 1997; 96: 396–399.CrossrefMedlineGoogle Scholar23 Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signaling. Nature. 1998; 394: 200–203.CrossrefMedlineGoogle Scholar24 Schonbeck U, Sukhova GK, Shimizu K, Mach F, Libby P. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci U S A. 2000; 97: 7458–7463.CrossrefMedlineGoogle Scholar25 Croce K, Libby P. Intertwining of thrombosis and inflammation in atherosclerosis. Curr Opin Hematol. 2007; 14: 55–61.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kandelouei T, Abbasifard M, Imani D, Aslani S, Razi B, Fasihi M, Shafiekhani S, Mohammadi K, Jamialahmadi T, Reiner Ž, Sahebkar A and Ugusman A (2022) Effect of Statins on Serum level of hs-CRP and CRP in Patients with Cardiovascular Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials, Mediators of Inflammation, 10.1155/2022/8732360, 2022, (1-20), Online publication date: 28-Jan-2022. Sato-Okabayashi Y, Isoda K, Heissig B, Kadoguchi T, Akita K, Kitamura K, Shimada K, Hattori K and Daida H (2020) Low-dose oral cyclophosphamide therapy reduces atherosclerosis progression by decreasing inflammatory cells in a murine model of atherosclerosis, IJC Heart & Vasculature, 10.1016/j.ijcha.2020.100529, 28, (100529), Online publication date: 1-Jun-2020. Liuzzo G, Pedicino D, Flego D and Crea F (2019) Inflammation and Atherothrombosis Clinical Immunology, 10.1016/B978-0-7020-6896-6.00069-7, (935-946.e1), . Oikonomou E, Latsios G, Vogiatzi G and Tousoulis D (2018) Atherosclerotic Plaque Coronary Artery Disease, 10.1016/B978-0-12-811908-2.00003-9, (31-41), . Tajbakhsh A, Rezaee M, Kovanen P and Sahebkar A (2018) Efferocytosis in atherosclerotic lesions: Malfunctioning regulatory pathways and control mechanisms, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2018.02.003, 188, (12-25), Online publication date: 1-Aug-2018. Gancheva R, Kundurdjiev A, Ivanova M, Kundurzhiev T and Kolarov Z (2016) Evaluation of cardiovascular risk in stages of gout by a complex multimodal ultrasonography, Rheumatology International, 10.1007/s00296-016-3556-6, 37:1, (121-130), Online publication date: 1-Jan-2017. Jia S, Gao K and Zhao M (2017) Epigenetic regulation in monocyte/macrophage: A key player during atherosclerosis, Cardiovascular Therapeutics, 10.1111/1755-5922.12262, 35:3, (e12262), Online publication date: 1-Jun-2017. de Bruin R, Shiue L, Prins J, de Boer H, Singh A, Fagg W, van Gils J, Duijs J, Katzman S, Kraaijeveld A, Böhringer S, Leung W, Kielbasa S, Donahue J, van der Zande P, Sijbom R, van Alem C, Bot I, van Kooten C, Jukema J, Van Esch H, Rabelink T, Kazan H, Biessen E, Ares M, van Zonneveld A and van der Veer E (2016) Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression, Nature Communications, 10.1038/ncomms10846, 7:1, Online publication date: 1-Apr-2016. De Luca L and Tomai F (2016) Biomarkers of Coronary Plaque Composition and Vulnerability Biomarkers in Cardiovascular Disease, 10.1007/978-94-007-7678-4_44, (897-913), . Chen J, Li Q, Li J and Maitz M (2016) The effect of anti-CD34 antibody orientation control on endothelial progenitor cell capturing cardiovascular devices, Journal of Bioactive and Compatible Polymers, 10.1177/0883911516637376, 31:6, (583-599), Online publication date: 1-Nov-2016. Di Gregoli K, George S, Newby A and Johnson J (2015) Differential effects of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 on atherosclerosis and monocyte/macrophage invasion, Cardiovascular Research, 10.1093/cvr/cvv268, 109:2, (318-330), Online publication date: 1-Feb-2016. Arévalo-Lorido J (2016) Clinical relevance for lowering C-reactive protein with statins, Annals of Medicine, 10.1080/07853890.2016.1197413, 48:7, (516-524), Online publication date: 2-Oct-2016. De Luca L and Tomai F (2015) Biomarkers of Coronary Plaque Composition and Vulnerability Biomarkers in Cardiovascular Disease, 10.1007/978-94-007-7741-5_44-1, (1-17), . Golden J, Groft S, Squeri M, Debanne S, Ward N, McCormick T and Cooper K (2015) Chronic Psoriatic Skin Inflammation Leads to Increased Monocyte Adhesion and Aggregation, The Journal of Immunology, 10.4049/jimmunol.1402307, 195:5, (2006-2018), Online publication date: 1-Sep-2015. Chen J, Li Q, Xu J, Zhang L, Maitz M and Li J (2015) Thromboresistant and rapid-endothelialization effects of dopamine and staphylococcal protein A mediated anti-CD34 coating on 316L stainless steel for cardiovascular devices, Journal of Materials Chemistry B, 10.1039/C4TB01825G, 3:13, (2615-2623) Chmielewski M, Lindholm B and Stenvinkel P (2015) Vascular Effects of Inflammation and Oxidative Stress in CKD Cardio-Renal Clinical Challenges, 10.1007/978-3-319-09162-4_6, (51-59), . Koller L, Kleber M, Goliasch G, Sulzgruber P, Scharnagl H, Silbernagel G, Grammer T, Delgado G, Tomaschitz A, Pilz S, März W and Niessner A (2014) C-reactive protein predicts mortality in patients referred for coronary angiography and symptoms of heart failure with preserved ejection fraction, European Journal of Heart Failure, 10.1002/ejhf.104, 16:7, (758-766), Online publication date: 1-Jul-2014. Niccoli G, Liuzzo G, Montone R and Crea F (2014) Advances in mechanisms, imaging and management of the unstable plaque, Atherosclerosis, 10.1016/j.atherosclerosis.2014.01.036, 233:2, (467-477), Online publication date: 1-Apr-2014. Eberlé D, Luk F, Kim R, Olivas V, Kumar N, Posada J, Li K, Gaudreault N, Rapp J and Raffai R (2013) Inducible Apoe Gene Repair in Hypomorphic ApoE Mice Deficient in the Low-Density Lipoprotein Receptor Promotes Atheroma Stabilization with a Human-Like Lipoprotein Profile, Arteriosclerosis, Thrombosis, and Vascular Biology, 33:8, (1759-1767), Online publication date: 1-Aug-2013. Ma X, Ma C and Zheng X (2013) MicroRNA-155 in the Pathogenesis of Atherosclerosis: A Conflicting Role?, Heart, Lung and Circulation, 10.1016/j.hlc.2013.05.651, 22:10, (811-818), Online publication date: 1-Oct-2013. Yousuf O, Mohanty B, Martin S, Joshi P, Blaha M, Nasir K, Blumenthal R and Budoff M (2013) High-Sensitivity C-Reactive Protein and Cardiovascular Disease, Journal of the American College of Cardiology, 10.1016/j.jacc.2013.05.016, 62:5, (397-408), Online publication date: 1-Jul-2013. Crea F and Liuzzo G (2013) Pathogenesis of Acute Coronary Syndromes, Journal of the American College of Cardiology, 10.1016/j.jacc.2012.07.064, 61:1, (1-11), Online publication date: 1-Jan-2013. Libby P (2013) Atherosclerosis Vascular Medicine: A Companion to Braunwald's Heart Disease, 10.1016/B978-1-4377-2930-6.00008-2, (111-125), . Della Bona R, Cardillo M, Leo M, Biasillo G, Gustapane M, Trotta F and Biasucci L (2013) Polymorphonuclear neutrophils and instability of the atherosclerotic plaque: a causative role?, Inflammation Research, 10.1007/s00011-013-0617-0, 62:6, (537-550), Online publication date: 1-Jun-2013. Alexander M, Murgai M, Moehle C and Owens G (2012) Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms, Physiological Genomics, 10.1152/physiolgenomics.00160.2011, 44:7, (417-429), Online publication date: 1-Apr-2012. Chen J, Cao J, Wang J, Maitz M, Guo L, Zhao Y, Li Q, Xiong K and Huang N (2012) Biofunctionalization of titanium with PEG and anti-CD34 for hemocompatibility and stimulated endothelialization, Journal of Colloid and Interface Science, 10.1016/j.jcis.2011.11.039, 368:1, (636-647), Online publication date: 1-Feb-2012. Raffai R (2012) Apolipoprotein E regulation of myeloid cell plasticity in atherosclerosis, Current Opinion in Lipidology, 10.1097/MOL.0b013e328356f967, 23:5, (471-478), Online publication date: 1-Oct-2012. Libby P (2012) The Vascular Biology of Atherosclerosis Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 10.1016/B978-1-4377-0398-6.00043-3, (897-913), . Thorp E, Subramanian M and Tabas I (2011) The role of macrophages and dendritic cells in the clearance of apoptotic cells in advanced atherosclerosis, European Journal of Immunology, 10.1002/eji.201141719, 41:9, (2515-2518), Online publication date: 1-Sep-2011. Thorp E, Iwawaki T, Miura M and Tabas I (2011) A reporter for tracking the UPR in vivo reveals patterns of temporal and cellular stress during atherosclerotic progression, Journal of Lipid Research, 10.1194/jlr.D012492, 52:5, (1033-1038), Online publication date: 1-May-2011. Hayashi C, Viereck J, Hua N, Phinikaridou A, Madrigal A, Gibson F, Hamilton J and Genco C (2011) Porphyromonas gingivalis accelerates inflammatory atherosclerosis in the innominate artery of ApoE deficient mice, Atherosclerosis, 10.1016/j.atherosclerosis.2010.12.009, 215:1, (52-59), Online publication date: 1-Mar-2011. Libby P and Crea F (2010) Clinical implications of inflammation for cardiovascular primary prevention, European Heart Journal, 10.1093/eurheartj/ehq022, 31:7, (777-783), Online publication date: 1-Apr-2010. Lin J, Li M, Wang Z, He S, Ma X and Li D (2010) The role of CD4+CD25+ regulatory T cells in macrophage-derived foam-cell formation, Journal of Lipid Research, 10.1194/jlr.D000497, 51:5, (1208-1217), Online publication date: 1-May-2010. Croce K and Libby P (2010) Stirring the soup of innate immunity in the acute coronary syndromes, European Heart Journal, 10.1093/eurheartj/ehq085, 31:12, (1430-1432), Online publication date: 2-Jun-2010. Rogacev K and Heine G (2010) Human monocyte heterogeneity–a nephrological perspective, Néphrologie & Thérapeutique, 10.1016/j.nephro.2010.01.008, 6:4, (219-225), Online publication date: 1-Jul-2010. Thorp E (2010) Mechanisms of failed apoptotic cell clearance by phagocyte subsets in cardiovascular disease, Apoptosis, 10.1007/s10495-010-0516-6, 15:9, (1124-1136), Online publication date: 1-Sep-2010. Robbins C and Swirski F (2010) The multiple roles of monocyte subsets in steady state and inflammation, Cellular and Molecular Life Sciences, 10.1007/s00018-010-0375-x, 67:16, (2685-2693), Online publication date: 1-Aug-2010. Libby P, Okamoto Y, Rocha V and Folco E (2010) Inflammation in Atherosclerosis: Transition From Theory to Practice, Circulation Journal, 10.1253/circj.CJ-09-0706, 74:2, (213-220), . Bobryshev Y (2010) Dendritic cells and their role in atherogenesis, Laboratory Investigation, 10.1038/labinvest.2010.94, 90:7, (970-984), Online publication date: 1-Jul-2010. Saha P, Modarai B, Humphries J, Mattock K, Waltham M, Burnand K and Smith A (2009) The monocyte/macrophage as a therapeutic target in atherosclerosis, Current Opinion in Pharmacology, 10.1016/j.coph.2008.12.017, 9:2, (109-118), Online publication date: 1-Apr-2009. Huo Y and Xia L (2009) P-selectin Glycoprotein Ligand-1 Plays a Crucial Role in the Selective Recruitment of Leukocytes Into the Atherosclerotic Arterial Wall, Trends in Cardiovascular Medicine, 10.1016/j.tcm.2009.07.006, 19:4, (140-145), Online publication date: 1-May-2009. Libby P, Ridker P and Hansson G (2009) Inflammation in Atherosclerosis, Journal of the American College of Cardiology, 10.1016/j.jacc.2009.09.009, 54:23, (2129-2138), Online publication date: 1-Dec-2009. Auffray C, Sieweke M and Geissmann F (2009) Blood Monocytes: Development, Heterogeneity, and Relationship with Dendritic Cells, Annual Review of Immunology, 10.1146/annurev.immunol.021908.132557, 27:1, (669-692), Online publication date: 1-Apr-2009. Shimada K (2009) Immune System and Atherosclerotic Disease, Circulation Journal, 10.1253/circj.CJ-09-0277, 73:6, (994-1001), . Johnson J and Newby A (2009) Macrophage heterogeneity in atherosclerotic plaques, Current Opinion in Lipidology, 10.1097/MOL.0b013e3283309848, 20:5, (370-378), Online publication date: 1-Oct-2009. Newby A (2008) Metalloproteinase Expression in Monocytes and Macrophages and its Relationship to Atherosclerotic Plaque Instability, Arteriosclerosis, Thrombosis, and Vascular Biology, 28:12, (2108-2114), Online publication date: 1-Dec-2008. Chaulin A and Grigoryeva J (2020) Inflammation in Atherosclerosis: From Theory to Practice, Bulletin of Science and Practice, 10.33619/2414-2948/59/21, 6:10, (186-205) Yang J, Li C, Zheng Y, Gao J, Liu Y, Wang J, Song J, Zhou Q, Meng X, Zhang K, Wang W, Shao C and Tang Y (2022) The Association Between High-Sensitivity C-Reactive Protein/Albumin Ratio and Cardiovascular Prognosis in Patients Undergoing Percutaneous Coronary Intervention, Angiology, 10.1177/00033197221110715, (000331972211107) Szewc M, Markiewicz-Gospodarek A, Górska A, Chilimoniuk Z, Rahnama M, Radzikowska-Buchner E, Strzelec-Pawelczak K, Bakiera J and Maciejewski R (2022) The Role of Zinc and Copper in Platelet Activation and Pathophysiological Thrombus Formation in Patients with Pulmonary Embolism in the Course of SARS-CoV-2 Infection, Biology, 10.3390/biology11050752, 11:5, (752) Hong L, Xue Q and Shao H (2021) Inflammatory Markers Related to Innate and Adaptive Immunity in Atherosclerosis: Implications for Disease Prediction and Prospective Therapeutics, Journal of Inflammation Research, 10.2147/JIR.S294809, Volume 14, (379-392) Wildgruber M, Lee H, Chudnovskiy A, Yoon T, Etzrodt M, Pittet M, Nahrendorf M, Croce K, Libby P, Weissleder R, Swirski F and Means T (2009) Monocyte Subset Dynamics in Human Atherosclerosis Can Be Profiled with Magnetic Nano-Sensors, PLoS ONE, 10.1371/journal.pone.0005663, 4:5, (e5663) June 24, 2008Vol 117, Issue 25 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.108.783068PMID: 18574058 Originally publishedJune 24, 2008 KeywordsendotheliumatherosclerosisEditorialsplaquePDF download Advertisement SubjectsCell Biology/Structural BiologyPathophysiology