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• W2146925456 abstract "HomeCirculationVol. 122, No. 18Neutrophils, Hypercholesterolemia, and Atherogenesis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBNeutrophils, Hypercholesterolemia, and Atherogenesis Stanley L. Hazen, MD, PhD Stanley L. HazenStanley L. Hazen From the Center for Cardiovascular Diagnostics and Prevention, Departments of Cell Biology and Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio. Search for more papers by this author Originally published18 Oct 2010https://doi.org/10.1161/CIRCULATIONAHA.110.984062Circulation. 2010;122:1786–1788Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 18, 2010: Previous Version 1 A critical role for hypercholesterolemia in the pathogenesis of atherosclerosis is firmly established. However, we still have much to learn about how hypercholesterolemia leads to the development of atherosclerotic heart disease and the spectrum of cellular participants involved. Atherosclerosis is viewed as a chronic inflammatory process, with our focus of attention dwelling on the role of cells recognized within the artery wall, including endothelial cells, monocyte-derived cells, and T lymphocytes.1–3 Hypercholesterolemia-induced activation of each of these cells has been mechanistically linked to multiple early processes in atherosclerosis, including upregulation of key adhesion proteins, chemokines, and cytokines that cumulatively orchestrate inflammatory cell trafficking into the vessel wall.4 A critical role for neutrophils, however, in the early atherosclerotic process has been conspicuously absent from the mainstream line of thought, no doubt because neutrophils are rarely observed in early atherosclerotic plaque compared with other inflammatory cell types.Article see p 1837Interestingly, a growing body of evidence points toward participation of neutrophils in later stages of atherosclerotic heart disease and its acute complications. Examination of both coronary artery segments obtained at autopsy and atherectomy specimens from subjects with unstable angina confirms that neutrophil infiltration is common within culprit lesions in subjects who experience an acute coronary event.5 Similarly, examination of human carotid atherosclerotic plaques has revealed that high neutrophil numbers are strongly associated with histopathological features of rupture-prone lesions, suggesting a role for neutrophils in plaque destabilization.6 Evidence for the involvement of neutrophils in plaque vulnerability has also come from both biochemical and immunohistochemical analyses of culprit plaques within human carotid endarterectomy specimens. Multiple neutrophil-specific proteases with links to matrix protein degradation such as elastase, neutrophil gelatinase–associated lipocalin, matrix metalloproteinase-9, CD66b, and proteinase 3 both colocalize with intralesional sites of hemorrhage and are positively correlated with the presence of additional neutrophil proteins such as α1-antitrypsin/elastase complexes, myeloperoxidase, and α-defensins.7 Evidence of neutrophil activation, as monitored by a reduction in leukocyte myeloperoxidase content across the coronary vasculature (a so-called transcoronary inflammatory gradient), has been directly observed in patients with unstable angina.8 Additionally, myeloperoxidase release, presumably via neutrophil activation, has also been reported as an early event in acute myocardial infarction, apparently preceding myocardial injury.9 Elevated systemic levels of myeloperoxidase, the most abundant protein in neutrophils, are associated with enhanced incident risk for major adverse cardiac events among subjects who present with chest pain or acute coronary syndrome,10,11 and myeloperoxidase and other neutrophil granule proteins are present within human atherosclerotic lesions.12–14 Thus, evolving evidence suggests neutrophil involvement in atherosclerotic plaque progression and acute plaque destabilization/vulnerability.Is there a role then for neutrophils in very early stages of atherosclerosis mediated via hypercholesterolemia? Interestingly, studies from nearly 3 decades ago in nonhuman primates suggested so. The time course of cellular recruitment into fatty streaks induced by a high-cholesterol diet was examined through detailed histopathological examination of the early cellular components of aortic fatty streaks in cholesterol-fed African green monkeys. Surprisingly, Although the anticipated cellular participants were observed within fatty streaks, after a high-cholesterol diet, the majority of lesions examined showed intimal neutrophils.15 It has taken several decades, but further support for a role for neutrophils in atherogenesis has recently been reported. Zernecke et al16 induced neutrophil depletion via antibody administration and observed marked decreased atherosclerotic lesion size in Apoe−/− mice. The chemokine receptor CXCR4 and its ligand CXCL12 (stromal-derived factor 1) play a critical role in regulating both bone marrow neutrophil emigration and resorption of senescent neutrophils back to the bone marrow.17,18 In further studies, Zernecke et al16 induced elevations in neutrophil levels by modulation of the CXCR4/CXCL12 axes and observed significant increases in both atherosclerotic lesion and necrotic core area size. In additional recent studies in Apoe−/− mice, fluorescently tagged neutrophils and monocytes were used in combination with flow cytometry, confocal microscopy, and intravital microscopy. Surprisingly, neutrophilic granulocytes were shown to serve as a major cellular component of atherosclerotic lesions in Apoe−/− mice, particularly within shoulder regions where they may even outnumber monocyte/macrophages.19 Moreover, the majority of leukocytes interacting with endothelium on lesion shoulders are neutrophils, suggesting a significant recruitment of these cells to plaque.19In this issue of Circulation, Drechsler and colleagues20 add substantially to this evolving story and provide convincing data to support a role for hypercholesterolemia-induced neutrophilia as a critical enabling process in early stages of atherosclerosis. Apoe−/− mice fed a high-fat diet demonstrated neutrophilia, with circulating neutrophil levels correlating with early atherosclerotic lesions. The mechanisms through which a high-fat diet elevated peripheral neutrophil numbers were shown to be multifactorial, including stimulation of granulopoiesis via tumor necrosis factor– and interleukin-17–mediated generation of granulocyte colony-stimulating factor, enhanced bone marrow mobilization (presumably via higher levels of CXCL1), and reduced peripheral clearance of senescent neutrophils (presumably via reduced CXCL12). Fluorescence-activated cell sorter analysis of digested aortas from mice fed a high-fat diet for different periods of time showed that neutrophils were prominent cellular infiltrates within the first month, with rapid reductions in numbers with longer durations of diet. Importantly, both intravital microscopy studies of large arteries (carotid) in monocyte-depleted Lysmegfp/egfpApoe−/− mice, in which only neutrophils are fluorescent, and immunohistochemical analyses (with neutrophil-specific marker Lys6G) of aortic roots of Apoe−/− mice on a high-fat diet for 1 month confirmed early transluminal infiltration of neutrophils. Through the use of multiple individual genetic knockouts, roles for CCR1, CCR2, CCR5, and CXCR2 were shown to be critical for early neutrophilic artery infiltration. Differential presentation of platelet-derived CCL5, the ligand for CCR1 and CCR5, was shown to be the underlying cause of the neutrophil recruitment specifically to the larger (carotid) artery through multiple approaches, including the use of selective platelet depletion, treatment with an antagonist to P-selectin, or treatment with an inhibitor to platelet glycoprotein IIb/IIIa. Finally, the link between aortic neutrophil infiltration and early atherosclerosis was demonstrated by selectively depleting neutrophils in Apoe−/− mice at differing time points. Significant reductions (≈50%) in aortic root lesions were observed only at early (eg, 1 month) time points.The studies by Drechsler et al do not reveal the underlying mechanism through which hypercholesterolemia-induced neutrophil recruitment promotes early atherosclerotic changes. However, they do point toward new potential avenues for therapeutic targeting. The role of CCR1 and CCR5 for neutrophilic recruitment selectively to arterial versus venous sites represents one potential option. Numerous neutrophil proteins now serve as candidates for both further investigation and therapeutic targeting. Neutrophil granule proteins have been shown to play a role in recruitment of inflammatory monocytes,21 and granule proteins like myeloperoxidase show numerous mechanistic links with atherosclerotic heart disease at multiple stages in the evolution of the atherosclerotic process.22 Whether or not interfering with neutrophil involvement in atherosclerotic heart disease development and its complications is a successful therapeutic approach in humans remains to be determined.Sources of FundingDr Hazen is supported by funding from the National Institutes of Health.DisclosuresDr Hazen reports being listed as coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Dr Hazen reports having been paid as a consultant for the following companies: Abbott, AstraZeneca Pharmaceuticals LP, BG Medicine, Inc, Merck & Co, Inc, Pfizer Inc, Cleveland Heart Laboratory, Inc, Esperion, Liposcience, and Takeda. Dr Hazen reports receiving research funds from Abbott, Esperion, Liposcience, and Cleveland Heart Laboratory Inc. Dr Hazen reports having the right to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics and the following companies: Cleveland Heart Laboratory, Inc, Abbott Laboratories, Inc, Biosite Inc, Frantz Biomarkers, LLC, and Siemens.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Stanley L. Hazen, MD, PhD, Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, 9500 Euclid Ave, Desk NE1-10, Cleveland, OH 44195.[email protected]orgReferences1. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340:115–126.CrossrefMedlineGoogle Scholar2. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352:1685–1695.CrossrefMedlineGoogle Scholar3. Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008; 8:802–815.CrossrefMedlineGoogle Scholar4. Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell. 2001; 104:503–516.CrossrefMedlineGoogle Scholar5. Naruko T, Ueda M, Haze K, van der Wal AC, van der Loos CM, Itoh A, Komatsu R, Ikura Y, Ogami M, Shimada Y, Ehara S, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE. Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation. 2002; 106:2894–2900.LinkGoogle Scholar6. Ionita MG, van den Borne P, Catanzariti LM, Moll FL, de Vries JP, Pasterkamp G, Vink A, de Kleijn DP. High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions. Arterioscler Thromb Vasc Biol. 2010; 30:1842–1848.LinkGoogle Scholar7. Leclercq A, Houard X, Philippe M, Ollivier V, Sebbag U, Meilhac O, Michel JB. Involvement of intraplaque hemorrhage in atherothrombosis evolution via neutrophil protease enrichment. J Leukoc Biol. 2007; 82:1420–1429.CrossrefMedlineGoogle Scholar8. Buffon A, Biasucci LM, Liuzzo G, D'Onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med. 2002; 347:5–12.CrossrefMedlineGoogle Scholar9. Goldmann BU, Rudolph V, Rudolph TK, Holle AK, Hillebrandt M, Meinertz T, Baldus S. Neutrophil activation precedes myocardial injury in patients with acute myocardial infarction. Free Radic Biol Med. 2009; 47:79–83.CrossrefMedlineGoogle Scholar10. Brennan ML, Penn MS, van Lente F, Nambi V, Shishehbor MH, Aviles RJ, Goormastic M, McErlean ES, Topol EJ, Nissen SE, Hazen SL. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med. 2003; 349:1595–1604.CrossrefMedlineGoogle Scholar11. Baldus S, Heeschen C, Meinertz T, Zeiher AM, Eiserich JP, Münzel T, Simoons ML, Hamm CWCAPTURE Investigators. 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The cell population of aortic fatty streaks in African green monkeys with special reference to granulocytic cells: an ultrastructural study. Atherosclerosis. 1982; 43:259–275.CrossrefMedlineGoogle Scholar16. Zernecke A, Bot I, Talab YD, Shagdarsuren E, Bidzhekov K, Meiler S, Krohn R, Schober A, Sperandio M, Soehnlein O, Bornemann J, Tacke F, Biessen EA, Weber C. Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res. 2008; 102:209–217.LinkGoogle Scholar17. Link DC. Neutrophil homeostasis: a new role for stromal cell-derived factor-1. Immunol Res. 2005; 32:169–178.CrossrefMedlineGoogle Scholar18. Christopher MJ, Link DC. Regulation of neutrophil homeostasis. Curr Opin Hematol. 2007; 14:3–8.CrossrefMedlineGoogle Scholar19. Rotzius P, Thams S, Soehnlein O, Kenne E, Tseng CN, Björkström NK, Malmberg KJ, Lindbom L, Eriksson EE. Distinct infiltration of neutrophils in lesion shoulders in ApoE−/− mice. Am J Pathol. 2010; 177:493–500.CrossrefMedlineGoogle Scholar20. Drechsler M, Megens RTA, van Zandvoort M, Weber C, Soehnlein O. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation. 2010; 122:1837–1845.LinkGoogle Scholar21. Soehnlein O, Lindbom L, Weber C. Mechanisms underlying neutrophil-mediated monocyte recruitment. Blood. 2009; 114:4613–4623.CrossrefMedlineGoogle Scholar22. Nicholls SJ, Hazen SL. Myeloperoxidase, modified lipoproteins, and atherogenesis. J Lipid Res. 2009; 50:S346–S351.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Oliveira D, Diniz S, Pereira R, Gonçalves I, Rennó A, Gorjão R, Vieira E, C. Ferreira A and Okuyama C (2021) Effectiveness of a new rutin Cu(II) complex in the prevention of lipid peroxidation and hepatotoxicity in hypercholesterolemic rats, Journal of Food Biochemistry, 10.1111/jfbc.13999, 46:3, Online publication date: 1-Mar-2022. Zhou S, Liu S, Liu X and Zhuang W (2020) Bioinformatics Gene Analysis of Potential Biomarkers and Therapeutic Targets for Unstable Atherosclerotic Plaque-Related Stroke, Journal of Molecular Neuroscience, 10.1007/s12031-020-01725-2, 71:5, (1031-1045), Online publication date: 1-May-2021. Strassheim D, Dempsey E, Gerasimovskaya E, Stenmark K and Karoor V (2019) Role of Inflammatory Cell Subtypes in Heart Failure, Journal of Immunology Research, 10.1155/2019/2164017, 2019, (1-9), Online publication date: 2-Sep-2019. Liberale L, Bertolotto M, Carbone F, Contini P, Wüst P, Spinella G, Pane B, Palombo D, Bonaventura A, Pende A, Mach F, Dallegri F, Camici G and Montecucco F (2018) Resistin exerts a beneficial role in atherosclerotic plaque inflammation by inhibiting neutrophil migration, International Journal of Cardiology, 10.1016/j.ijcard.2018.07.112, 272, (13-19), Online publication date: 1-Dec-2018. Escate R, Padro T, Borrell-Pages M, Suades R, Aledo R, Mata P and Badimon L (2016) Macrophages of genetically characterized familial hypercholesterolaemia patients show up-regulation of LDL-receptor-related proteins, Journal of Cellular and Molecular Medicine, 10.1111/jcmm.12993, 21:3, (487-499), Online publication date: 1-Mar-2017. Suades R, Padró T, Alonso R, López-Miranda J, Mata P and Badimon L (2017) Circulating CD45+/CD3+ lymphocyte-derived microparticles map lipid-rich atherosclerotic plaques in familial hypercholesterolaemia patients, Thrombosis and Haemostasis, 10.1160/TH13-07-0612, 111:01, (111-121), . Nussbaum C, Klinke A, Adam M, Baldus S and Sperandio M (2013) Myeloperoxidase: A Leukocyte-Derived Protagonist of Inflammation and Cardiovascular Disease, Antioxidants & Redox Signaling, 10.1089/ars.2012.4783, 18:6, (692-713), Online publication date: 20-Feb-2013. Milne G, Yin H, Hardy K, Davies S and Roberts L (2011) Isoprostane Generation and Function, Chemical Reviews, 10.1021/cr200160h, 111:10, (5973-5996), Online publication date: 12-Oct-2011. Villar I, Scotland R, Khambata R, Chan M, Duchene J, Sampaio A, Perretti M, Hobbs A and Ahluwalia A (2011) Suppression of Endothelial P-Selectin Expression Contributes to Reduced Cell Trafficking in Females, Arteriosclerosis, Thrombosis, and Vascular Biology, 31:5, (1075-1083), Online publication date: 1-May-2011. November 2, 2010Vol 122, Issue 18 Advertisement Article InformationMetrics © 2010 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.110.984062PMID: 20956213 Originally publishedOctober 18, 2010 KeywordsatherogenesisEditorialsinflammationatherosclerosisneutrophilPDF download Advertisement SubjectsAnimal Models of Human DiseasePathophysiology" @default.
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