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Heart and Vessels
Published in: Heart and Vessels 12/2018

01-12-2018 | Original Article

CD34+ circulating cells display signs of immune activation in patients with acute coronary syndrome

Authors: Lisa Riesinger, Michael Saemisch, Markus Nickmann, Heiko Methe

Published in: Heart and Vessels | Issue 12/2018

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Abstract

Bone marrow-derived endothelial progenitor cells (EPC) are released into the peripheral blood in situations of vascular repair/angiogenesis. Regulation of vascular repair and angiogenesis by EPC depends not only on the number of circulating EPC but also on their functionality. As endothelial cells can act as antigen-presenting cells in coronary artery disease (CAD), we postulated that EPC can be immune activated here as well. CD34+-EPC were isolated from peripheral blood of patients with ST-elevation myocardial infarction (STEMI, n = 12), non-STEMI/unstable angina (UA, n = 15), and stable CAD (SA, n = 18). Expression of HLA-DR, adhesion and costimulatory molecules by isolated CD34+-EPC were compared with levels in healthy controls (n = 18). There were no significant differences in VCAM-1 and CD80 expression by peripheral circulating CD34+-EPC between the four groups, yet expression of CD86 was highest in UA (p < 0.05). ICAM-1 expression was lowest in SA (p < 0.01). CD34+-EPC constitutively expressed HLA-DR across all groups. Of note, patients pretreated with HMG-CoA reductase inhibitors exhibited lower expression of VCAM-1 by CD34+-EPC throughout all patient groups; furthermore, statins significantly limited ex vivo-induced upregulation of ICAM-1 by TNF-alpha. To the best of our knowledge, this is the first study to examine the expression of immune markers in peripheral circulating CD34+-EPC ex vivo. We demonstrate that CD34+-EPC display different patterns of adhesion and costimulatory molecules in various states of CAD. Expression levels were affected by pretreatment with statins. Hence, immune activity of peripheral circulating CD34+ cells might play a pathophysiologic role in evolution of CAD.
Literature
1.
2.
Ribatti D, Nico B, Vacca A, Roncali L, Dammacco F (2002) Endothelial cell heterogeneity and organ specificity. J Hematother Stem Cell Res 11:81–90CrossRef
3.
Rubanyi GM (1993) The role of endothelium in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol 22(Suppl 4):S1–14CrossRef
4.
Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561PubMed
5.
Anter E, Chen K, Shapira OM, Karas RH, Keaney JF Jr (2005) p38 mitogen-activated protein kinase activates eNOS in endothelial cells by an estrogen receptor alpha-dependent pathway in response to black tea polyphenols. Circ Res 96:1072–1078CrossRef
6.
Upchurch GR Jr, Welch GN, Freedman JE, Fabian AJ, Pigazzi A, Scribner AM, Alpert CS, Keaney JF Jr, Loscalzo J (1997) High-dose heparin decreases nitric oxide production by cultured bovine endothelial cells. Circulation 95:2115–2121CrossRef
7.
Ando J, Kamiya A (1993) Blood flow and vascular endothelial cell function. Front Med Biol Eng 5:245–264PubMed
8.
Aird WC, Edelberg JM, Weiler-Guettler H, Simmons WW, Smith TW, Rosenberg RD (1997) Vascular bed-specific expression of an endothelial cell gene is programmed by the tissue microenvironment. J Cell Biol 138:1117–1124CrossRef
9.
Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126CrossRef
10.
Schwartz RS (1998) Pathophysiology of restenosis: interaction of thrombosis, hyperplasia, and/or remodeling. Am J Cardiol 81:14E–17ECrossRef
11.
Rogers C, Parikh S, Seifert P, Edelman ER (1996) Endogenous cell seeding. Remnant endothelium after stenting enhances vascular repair. Circulation 94:2909–2914CrossRef
12.
Hirsch EZ, Chisolm GM 3rd, White HM (1983) Reendothelialization and maintenance of endothelial integrity in longitudinal denuded tracks in the thoracic aorta of rats. Atherosclerosis 46:287–307CrossRef
13.
Reidy MA, Bowyer DE (1978) Distortion of endothelial repair. The effect of hypercholesterolaemia on regeneration of aortic endothelium following injury by endotoxin. A scanning electron microscope study. Atherosclerosis 29:459–466CrossRef
14.
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967CrossRef
15.
Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T (1999) Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5:434–438CrossRef
16.
Epstein SE, Stabile E, Kinnaird T, Lee CW, Clavijo L, Burnett MS (2004) Janus phenomenon: the interrelated tradeoffs inherent in therapies designed to enhance collateral formation and those designed to inhibit atherogenesis. Circulation 109:2826–2831CrossRef
17.
Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353:999–1007CrossRef
18.
Schwartzenberg S, Deutsch V, Maysel-Auslender S, Kissil S, Keren G, George J (2007) Circulating apoptotic progenitor cells: a novel biomarker in patients with acute coronary syndromes. Arterioscler Thromb Vasc Biol 27:e27–e31CrossRef
19.
Vartanian KB, Berny MA, McCarty OJ, Hanson SR, Hinds MT (2010) Cytoskeletal structure regulates endothelial cell immunogenicity independent of fluid shear stress. Am J Physiol Cell Physiol 298:C333–C341CrossRef
20.
Nickmann M, Saemisch M, Wilbert-Lampen U, Nickel T, Edelman ER, Methe H (2013) Cell matrix contact modifies endothelial major histocompatibility complex class II expression in high-glucose environment. Am J Physiol Heart Circ Physiol 305:H1592–H1599CrossRef
21.
Hess S, Methe H, Kim JO, Edelman ER (2009) NF-kappaB activity in endothelial cells is modulated by cell substratum interactions and influences chemokine-mediated adhesion of natural killer cells. Cell Transplant 18:261–273CrossRef
22.
Methe H, Hess S, Edelman ER (2007) Endothelial cell-matrix interactions determine maturation of dendritic cells. Eur J Immunol 37:1773–1784CrossRef
23.
Zani BG, Kojima K, Vacanti CA, Edelman ER (2008) Tissue-engineered endothelial and epithelial implants differentially and synergistically regulate airway repair. Proc Natl Acad Sci USA 105:7046–7051CrossRef
24.
Costa LF, Balcells M, Edelman ER, Nadler LM, Cardoso AA (2006) Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF-kappaB. Blood 107:285–292CrossRef
25.
Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Ting HH, O’Gara PT, Kushner FG, Ascheim DD, Brindis RG, Casey DE Jr, Chung MK, de Lemos JA, Diercks DB, Fang JC, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX (2016) 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 133:1135–1147CrossRef
26.
Richter G, Hayden-Ledbetter M, Irgang M, Ledbetter JA, Westermann J, Korner I, Daemen K, Clark EA, Aicher A, Pezzutto A (2001) Tumor necrosis factor-alpha regulates the expression of inducible costimulator receptor ligand on CD34(+) progenitor cells during differentiation into antigen presenting cells. J Biol Chem 276:45686–45693CrossRef
27.
Ryncarz RE, Anasetti C (1998) Expression of CD86 on human marrow CD34(+) cells identifies immunocompetent committed precursors of macrophages and dendritic cells. Blood 91:3892–3900PubMed
28.
Zeng W, Miyazato A, Chen G, Kajigaya S, Young NS, Maciejewski JP (2006) Interferon-gamma-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles. Blood 107:167–175CrossRef
29.
Umland O, Heine H, Miehe M, Marienfeld K, Staubach KH, Ulmer AJ (2004) Induction of various immune modulatory molecules in CD34(+) hematopoietic cells. J Leukoc Biol 75:671–679CrossRef
30.
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408CrossRef
31.
Fina L, Molgaard HV, Robertson D, Bradley NJ, Monaghan P, Delia D, Sutherland DR, Baker MA, Greaves MF (1990) Expression of the CD34 gene in vascular endothelial cells. Blood 75:2417–2426PubMed
32.
Hristov M, Weber C (2008) Endothelial progenitor cells in vascular repair and remodeling. Pharmacol Res 58:148–151CrossRef
33.
Brenes RA, Bear M, Jadlowiec C, Goodwin M, Hashim P, Protack CD, Ziegler KR, Li X, Model LS, Lv W, Collins MJ, Dardik A (2012) Cell-based interventions for therapeutic angiogenesis: review of potential cell sources. Vascular 20:360–368CrossRef
34.
Heiss C, Keymel S, Niesler U, Ziemann J, Kelm M, Kalka C (2005) Impaired progenitor cell activity in age-related endothelial dysfunction. J Am Coll Cardiol 45:1441–1448CrossRef
35.
Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348:593–600CrossRef
36.
Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, Pippen AM, Annex BH, Dong C, Taylor DA (2003) Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 108:457–463CrossRef
37.
Cohen KS, Cheng S, Larson MG, Cupples LA, McCabe EL, Wang YA, Ngwa JS, Martin RP, Klein RJ, Hashmi B, Ge Y, O’Donnell CJ, Vasan RS, Shaw SY, Wang TJ (2013) Circulating CD34(+) progenitor cell frequency is associated with clinical and genetic factors. Blood 121:e50–e56CrossRef
38.
Fadini GP, Losordo D, Dimmeler S (2012) Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res 110:624–637CrossRef
39.
Massa M, Rosti V, Ferrario M, Campanelli R, Ramajoli I, Rosso R, De Ferrari GM, Ferlini M, Goffredo L, Bertoletti A, Klersy C, Pecci A, Moratti R, Tavazzi L (2005) Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood 105:199–206CrossRef
40.
Cuadrado-Godia E, Regueiro A, Nunez J, Diaz-Ricard M, Novella S, Oliveras A, Valverde MA, Marrugat J, Ois A, Giralt-Steinhauer E, Sanchis J, Escolar G, Hermenegildo C, Heras M, Roquer J (2015) Endothelial progenitor cells predict cardiovascular events after atherothrombotic stroke and acute myocardial infarction. A PROCELL Substudy. PLoS One 10:e0132415CrossRef
41.
Mourino-Alvarez L, Calvo E, Moreu J, Padial LR, Lopez JA, Barderas MG, Gil-Dones F (2013) Proteomic characterization of EPCs and CECs “in vivo” from acute coronary syndrome patients and control subjects. Biochim Biophys Acta 1830:3030–3053CrossRef
42.
Gil-Dones F, Darde VM, Alonso-Orgaz S, Lopez-Almodovar LF, Mourino-Alvarez L, Padial LR, Vivanco F, Barderas MG (2012) Inside human aortic stenosis: a proteomic analysis of plasma. J Proteom 75:1639–1653CrossRef
43.
Darde VM, de la Cuesta F, Dones FG, Alvarez-Llamas G, Barderas MG, Vivanco F (2010) Analysis of the plasma proteome associated with acute coronary syndrome: does a permanent protein signature exist in the plasma of ACS patients? J Proteome Res 9:4420–4432CrossRef
44.
Methe H, Edelman ER (2006) Cell-matrix contact prevents recognition and damage of endothelial cells in states of heightened immunity. Circulation 114:I233–I238CrossRef
45.
Methe H, Hess S, Edelman ER (2008) The effect of three-dimensional matrix-embedding of endothelial cells on the humoral and cellular immune response. Semin Immunol 20:117–122CrossRef
46.
Methe H, Nugent HM, Groothuis A, Seifert P, Sayegh MH, Edelman ER (2005) Matrix embedding alters the immune response against endothelial cells in vitro and in vivo. Circulation 112:I89–I95PubMed
47.
Sandhu K, Mamas M, Butler R (2017) Endothelial progenitor cells: exploring the pleiotropic effects of statins. World J Cardiol 9:1–13CrossRef
48.
Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM (2001) HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 108:391–397CrossRef
49.
Hansson GK, Libby P, Schonbeck U, Yan ZQ (2002) Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 91:281–291CrossRef
50.
Sayegh MH, Turka LA (1998) The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 338:1813–1821CrossRef
51.
Seino K, Azuma M, Bashuda H, Fukao K, Yagita H, Okumura K (1995) CD86 (B70/B7-2) on endothelial cells co-stimulates allogeneic CD4+ T cells. Int Immunol 7:1331–1337CrossRef
52.
Maher SE, Karmann K, Min W, Hughes CC, Pober JS, Bothwell AL (1996) Porcine endothelial CD86 is a major costimulator of xenogeneic human T cells: cloning, sequencing, and functional expression in human endothelial cells. J Immunol 157:3838–3844PubMed
53.
Pober JS, Gimbrone MA Jr, Collins T, Cotran RS, Ault KA, Fiers W, Krensky AM, Clayberger C, Reiss CS, Burakoff SJ (1984) Interactions of T lymphocytes with human vascular endothelial cells: role of endothelial cells surface antigens. Immunobiology 168:483–494CrossRef
54.
Wu Y, Ip JE, Huang J, Zhang L, Matsushita K, Liew CC, Pratt RE, Dzau VJ (2006) Essential role of ICAM-1/CD18 in mediating EPC recruitment, angiogenesis, and repair to the infarcted myocardium. Circ Res 99:315–322CrossRef
55.
Langer H, May AE, Daub K, Heinzmann U, Lang P, Schumm M, Vestweber D, Massberg S, Schonberger T, Pfisterer I, Hatzopoulos AK, Gawaz M (2006) Adherent platelets recruit and induce differentiation of murine embryonic endothelial progenitor cells to mature endothelial cells in vitro. Circ Res 98:e2–10CrossRef
56.
Chavakis E, Aicher A, Heeschen C, Sasaki K, Kaiser R, El Makhfi N, Urbich C, Peters T, Scharffetter-Kochanek K, Zeiher AM, Chavakis T, Dimmeler S (2005) Role of beta2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med 201:63–72CrossRef
57.
Goon PK, Lip GY, Boos CJ, Stonelake PS, Blann AD (2006) Circulating endothelial cells, endothelial progenitor cells, and endothelial microparticles in cancer. Neoplasia 8:79–88CrossRef
58.
O’Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin CD et al (1993) Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest 92:945–951CrossRef
59.
Ley K, Huo Y (2001) VCAM-1 is critical in atherosclerosis. J Clin Invest 107:1209–1210CrossRef
60.
Werner N, Priller J, Laufs U, Endres M, Bohm M, Dirnagl U, Nickenig G (2002) Bone marrow-derived progenitor cells modulate vascular reendothelialization and neointimal formation: effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition. Arterioscler Thromb Vasc Biol 22:1567–1572CrossRef
61.
Oesterle A, Laufs U, Liao JK (2017) Pleiotropic effects of statins on the cardiovascular system. Circ Res 120:229–243CrossRef
62.
Methe H, Kim JO, Kofler S, Nabauer M, Weis M (2005) Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes. Arterioscler Thromb Vasc Biol 25:1439–1445CrossRef
63.
Solheim S, Seljeflot I, Arnesen H, Eritsland J, Eikvar L (2001) Reduced levels of TNF alpha in hypercholesterolemic individuals after treatment with pravastatin for 8 weeks. Atherosclerosis 157:411–415CrossRef
64.
Satoh M, Ishikawa Y, Takahashi Y, Itoh T, Minami Y, Nakamura M (2008) Association between oxidative DNA damage and telomere shortening in circulating endothelial progenitor cells obtained from metabolic syndrome patients with coronary artery disease. Atherosclerosis 198:347–353CrossRef
65.
Yoder MC (2012) Human endothelial progenitor cells. Cold Spring Harb Perspect Med 2:a006692CrossRef
66.
Fadini GP, de Kreutzenberg SV, Coracina A, Baesso I, Agostini C, Tiengo A, Avogaro A (2006) Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk. Eur Heart J 27:2247–2255CrossRef
67.
Fadini GP, Maruyama S, Ozaki T, Taguchi A, Meigs J, Dimmeler S, Zeiher AM, de Kreutzenberg S, Avogaro A, Nickenig G, Schmidt-Lucke C, Werner N (2010) Circulating progenitor cell count for cardiovascular risk stratification: a pooled analysis. PLoS One 5:e11488CrossRef
68.
Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89:E1–E7CrossRef
69.
Urbich C, Dimmeler S (2004) Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 95:343–353CrossRef
70.
Fadini GP, Baesso I, Albiero M, Sartore S, Agostini C, Avogaro A (2008) Technical notes on endothelial progenitor cells: ways to escape from the knowledge plateau. Atherosclerosis 197:496–503CrossRef
71.
Keymel S, Kalka C, Rassaf T, Yeghiazarians Y, Kelm M, Heiss C (2008) Impaired endothelial progenitor cell function predicts age-dependent carotid intimal thickening. Basic Res Cardiol 103:582–586CrossRef
72.
Scheubel RJ, Zorn H, Silber RE, Kuss O, Morawietz H, Holtz J, Simm A (2003) Age-dependent depression in circulating endothelial progenitor cells in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol 42:2073–2080CrossRef
Metadata
Title
CD34+ circulating cells display signs of immune activation in patients with acute coronary syndrome
Authors
Lisa Riesinger
Michael Saemisch
Markus Nickmann
Heiko Methe
Publication date
01-12-2018
Publisher
Springer Japan
Published in
Heart and Vessels / Issue 12/2018
Print ISSN: 0910-8327
Electronic ISSN: 1615-2573
DOI
https://doi.org/10.1007/s00380-018-1220-7

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