Reduced levels of circulating endothelial progenitor cells in acute myocardial infarction patients with diabetes or pre-diabetes: accompanying the glycemic continuum

Cardiovascular Diabetology

Carlos Fontes Ribeiro³  Lino Gonçalves⁴  Luís A Providência⁴  Guilherme Mariano Pêgo⁴  Artur Paiva²  Tiago Carvalheiro²  Ana Lopes²  Francisco Soares⁴  Ana Soares¹  Rosa Fernandes¹  Natália António⁴ 

[1] Center of Ophthalmology and Vision Sciences; Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, Portugal;Blood and Transplantation Center of Coimbra

[2]  Portuguese Institute of Blood and Transplantation, Coimbra, Portugal;Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal;Cardiology Department, University Hospital Center of Coimbra, Coimbra, Portugal

关键词: Homing;    Acute myocardial infarction;    Oral antidiabetic drugs;    Insulin;    Pre-diabetes;    Diabetes;    Endothelial progenitor cells;   

Others  :  794235
DOI  :  10.1186/1475-2840-13-101

 received in 2014-04-04, accepted in 2014-05-24,  发布年份 2014

【 摘 要 】

Background

Diabetic patients have a significantly worse prognosis after an acute myocardial infarction (AMI) than their counterparts. Previous studies have shown that the number of circulating endothelial progenitor cells (EPCs) significantly increase early after an AMI in normoglycemic patients. However, it is well known that type 2 diabetes mellitus (DM) is associated with impaired function and reduced circulating EPCs levels. Nonetheless, few studies have analyzed EPCs response of diabetics to an AMI and the EPC response of pre-diabetic patients has not been reported yet. Therefore, we hypothesized that in the acute phase of an AMI, diabetic and pre-diabetics have lower circulating EPCs levels than patients with normal glucose metabolism. We also evaluated the possible capacity of chronic antidiabetic treatment in the recovery of EPCs response to an AMI in diabetics.

Methods

One-hundred AMI patients were prospectively enrolled in the study. Using the high-performance flow cytometer FACSCanto II, circulating EPCs (CD45dimCD34+KDR+ and CD45dimCD133+KDR+ cells) were quantified, within the first 24 hours of admission. In addition, as an indirect functional parameter, we also analyzed the fraction of EPCs coexpressing the homing marker CXCR4.

Results

We found that in the acute phase of an AMI, diabetic patients presented significantly lower levels of circulating CD45dimCD34+KDR+ and CD45dimCD133+KDR+ EPCs by comparison with nondiabetics, with a parallel decrease in the subpopulations CXCR4+ (p < 0.001). Indeed, this study suggests that the impaired response of EPCs to an AMI is an early event in the natural history of DM, being present even in pre-diabetes. Our results, also demonstrated that numbers of all EPCs populations were inversely correlated with HbA1c (r = -0.432, p < 0.001 for CD45dimCD34+KDR+ cells). Finally, this study suggests that previous chronic insulin therapy (but not oral antidiabetic drugs) attenuate the deficient response of diabetic EPCs to an AMI.

Conclusion

This study indicates that there is a progressive decrease in EPCs levels, from pre-diabetes to DM, in AMI patients. Moreover, glycemic control seems to be determinant for circulating EPCs levels presented in the acute phase of an AMI and chronic insulin therapy may probably attenuate the deficit in EPCs pool seen in diabetics.

【 授权许可】

   
2014 António et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Harjai KJ, Stone GW, Boura J, Mattos L, Chandra H, Cox D, Grines L, O’Neill W, Grines C: Comparison of outcomes of diabetic and nondiabetic patients undergoing primary angioplasty for acute myocardial infarction. Am J Cardiol 2003, 91(9):1041-1045.
• [2]Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM: Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997, 275(5302):964-967.
• [3]Zampetaki A, Kirton JP, Xu Q: Vascular repair by endothelial progenitor cells. Cardiovasc Res 2008, 78(3):413-421.
• [4]Hristov M, Erl W, Weber PC: Endothelial progenitor cells: mobilization, differentiation, and homing. Arterioscler Thromb Vasc Biol 2003, 23(7):1185-1189.
• [5]Urbich C, Aicher A, Heeschen C, Dernbach E, Hofmann WK, Zeiher AM, Dimmeler S: Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol 2005, 39(5):733-742.
• [6]Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T: Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003, 348(7):593-600.
• [7]Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, Sasaki K, Shimada T, Oike Y, Imaizumi T: Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 2001, 103(23):2776-2779.
• [8]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: Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood 2005, 105(1):199-206.
• [9]Hamed S, Brenner B, Aharon A, Daoud D, Roguin A: Nitric oxide and superoxide dismutase modulate endothelial progenitor cell function in type 2 diabetes mellitus. Cardiovasc Diabetol 2009, 8:56.
• [10]Fadini GP, Miorin M, Facco M, Bonamico S, Baesso I, Grego F, Menegolo M, de Kreutzenberg SV, Tiengo A, Agostini C, Avogaro A: Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol 2005, 45(9):1449-1457.
• [11]Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC: Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 2002, 106(22):2781-2786.
• [12]Li H, Zhang X, Guan X, Cui X, Wang Y, Chu H, Cheng M: Advanced glycation end products impair the migration, adhesion and secretion potentials of late endothelial progenitor cells. Cardiovasc Diabetol 2012, 11:46.
• [13]DeFronzo RA, Abdul-Ghani M: Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am J Cardiol 2011, 108(3 Suppl):3B-24B.
• [14]Antonio N, Fernandes R, Rodriguez-Losada N, Jimenez-Navarro MF, Paiva A, de Teresa GE, Goncalves L, Ribeiro CF, Providencia LA: Stimulation of endothelial progenitor cells: a new putative effect of several cardiovascular drugs. Eur J Clin Pharmacol 2010, 66(3):219-230.
• [15]Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes HP, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J, Patrono C, Seferovic P, Uva MS, Taskinen MR, Tendera M, Tuomilehto J, Valensi P, Zamorano JL: ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 2013, 34(39):3035-3087.
• [16]American Diabetes Association: Diagnosis and classification of diabetes mellitus. Diabetes Care 2012, 35(Suppl 1):S64-S71.
• [17]Schmidt-Lucke C, Fichtlscherer S, Aicher A, Tschope C, Schultheiss HP, Zeiher AM, Dimmeler S: Quantification of circulating endothelial progenitor cells using the modified ISHAGE protocol. PLoS One 2010, 5(11):e13790.
• [18]Ingram DA, Caplice NM, Yoder MC: Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells. Blood 2005, 106(5):1525-1531.
• [19]Walter DH, Haendeler J, Reinhold J, Rochwalsky U, Seeger F, Honold J, Hoffmann J, Urbich C, Lehmann R, Arenzana-Seisdesdos F, Aicher A, Heeschen C, Fichtlscherer S, Zeiher AM, Dimmeler S: Impaired CXCR4 signaling contributes to the reduced neovascularization capacity of endothelial progenitor cells from patients with coronary artery disease. Circ Res 2005, 97(11):1142-1151.
• [20]Sutherland DR, Anderson L, Keeney M, Nayar R, Chin-Yee I: The ISHAGE guidelines for CD34+ cell determination by flow cytometry. International Society of Hematotherapy and Graft Engineering. J Hematother 1996, 5(3):213-226.
• [21]Sun JY, Zhai L, Li QL, Ye JX, Kang LN, Xie J, Xu B: Effects of ACE inhibition on endothelial progenitor cell mobilization and prognosis after acute myocardial infarction in type 2 diabetic patients. Clinics (Sao Paulo) 2013, 68(5):665-673.
• [22]Ling L, Shen Y, Wang K, Jiang C, Fang C, Ferro A, Kang L, Xu B: Worse clinical outcomes in acute myocardial infarction patients with type 2 diabetes mellitus: relevance to impaired endothelial progenitor cells mobilization. PLoS One 2012, 7(11):e50739.
• [23]Yeh ET, Zhang S, Wu HD, Korbling M, Willerson JT, Estrov Z: Transdifferentiation of human peripheral blood CD34+-enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. Circulation 2003, 108(17):2070-2073.
• [24]Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G: Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005, 353(10):999-1007.
• [25]Fortunato O, Spinetti G, Specchia C, Cangiano E, Valgimigli M, Madeddu P: Migratory activity of circulating progenitor cells and serum SDF-1alpha predict adverse events in patients with myocardial infarction. Circ Res 2013, 100(2):192-200.
• [26]Rosenson RS, Reasner CA: Therapeutic approaches in the prevention of cardiovascular disease in metabolic syndrome and in patients with type 2 diabetes. Curr Opin Cardiol 2004, 19(5):480-487.
• [27]Zhao CT, Wang M, Siu CW, Hou YL, Wang T, Tse HF, Yiu KH: Myocardial dysfunction in patients with type 2 diabetes mellitus: role of endothelial progenitor cells and oxidative stress. Cardiovasc Diabetol 2012, 11:147.
• [28]Fadini GP, Sartore S, Schiavon M, Albiero M, Baesso I, Cabrelle A, Agostini C, Avogaro A: Diabetes impairs progenitor cell mobilisation after hindlimb ischaemia-reperfusion injury in rats. Diabetologia 2006, 49(12):3075-3084.
• [29]Marfella R, Rizzo MR, Siniscalchi M, Paolisso P, Barbieri M, Sardu C, Savinelli A, Angelico N, Del Gaudio S, Esposito N, Rambaldi PF, D'Onofrio N, Mansi L, Mauro C, Paolisso G, Balestrieri ML: Peri-procedural tight glycemic control during early percutaneous coronary intervention up-regulates endothelial progenitor cell level and differentiation during acute ST-elevation myocardial infarction: effects on myocardial salvage. Int J Cardiol 2013, 168(4):3954-3962.
• [30]Chen MC, Chen CJ, Yang CH, Liu WH, Fang CY, Hsieh YK, Chang HW: Relationship of the percentage of circulating endothelial progenitor cell to the severity of coronary artery disease. Heart Vessels 2008, 23(1):47-52.
• [31]Bozdag-Turan I, Turan RG, Turan CH, Ludovicy S, Akin I, Kische S, Arsoy NS, Schneider H, Ortak J, Rehders T, Hermann T, Paranskaya L, Kohlschein P, Bastian M, Ulus AT, Sahin K, Ince H, Nienaber CA: Relation between the frequency of CD34(+) bone marrow derived circulating progenitor cells and the number of diseased coronary arteries in patients with myocardial ischemia and diabetes. Cardiovasc Diabetol 2011, 10:107.
• [32]Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S: Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001, 89(1):E1-E7.
• [33]Khan SS, Solomon MA, McCoy JP Jr: Detection of circulating endothelial cells and endothelial progenitor cells by flow cytometry. Cytometry B Clin Cytom 2005, 64(1):1-8.
• [34]Yoder MC: Human endothelial progenitor cells. Cold Spring Harb Perspect Med 2012, 2(7):a006692.
• [35]Handgretinger R, Gordon PR, Leimig T, Chen X, Buhring HJ, Niethammer D, Kuci S: Biology and plasticity of CD133+ hematopoietic stem cells. Ann N Y Acad Sci 2003, 996:141-151.
• [36]Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S: Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 2000, 95(3):952-958.
• [37]Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, Bosch-Marce M, Masuda H, Losordo DW, Isner JM, Asahara T: Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 2003, 107(9):1322-1328.
• [38]Barr EL, Zimmet PZ, Welborn TA, Jolley D, Magliano DJ, Dunstan DW, Cameron AJ, Dwyer T, Taylor HR, Tonkin AM, Wong TY, McNeil J, Shaw JE: Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation 2007, 116(2):151-157.
• [39]Fadini GP, Pucci L, Vanacore R, Baesso I, Penno G, Balbarini A, Di Stefano R, Miccoli R, de Kreutzenberg S, Coracina A, Tiengo A, Agostini C, Del Prato S, Avogaro A: Glucose tolerance is negatively associated with circulating progenitor cell levels. Diabetologia 2007, 50(10):2156-2163.
• [40]Dong L, Kang L, Ding L, Chen Q, Bai J, Gu R, Li L, Xu B: Insulin modulates ischemia-induced endothelial progenitor cell mobilization and neovascularization in diabetic mice. Microvasc Res 2011, 82(3):227-236.
• [41]Zhao L, Cao F, Yin T, Sun D, Cheng K, Zhang J, Wang H: Moderate dose insulin promotes function of endothelial progenitor cells. Cell Biol Int 2011, 35(3):215-220.
• [42]Humpert PM, Djuric Z, Zeuge U, Oikonomou D, Seregin Y, Laine K, Eckstein V, Nawroth PP, Bierhaus A: Insulin stimulates the clonogenic potential of angiogenic endothelial progenitor cells by IGF-1 receptor-dependent signaling. Mol Med 2008, 14(5–6):301-308.
• [43]Wang CH, Ting MK, Verma S, Kuo LT, Yang NI, Hsieh IC, Wang SY, Hung A, Cherng WJ: Pioglitazone increases the numbers and improves the functional capacity of endothelial progenitor cells in patients with diabetes mellitus. Am Heart J 2006, 152(6):1051. e1051-1058
• [44]Fadini GP, Boscaro E, Albiero M, Menegazzo L, Frison V, de Kreutzenberg S, Agostini C, Tiengo A, Avogaro A: The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care 2010, 33(7):1607-1609.
• [45]Pistrosch F, Herbrig K, Oelschlaegel U, Richter S, Passauer J, Fischer S, Gross P: PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells. Atherosclerosis 2005, 183(1):163-167.
• [46]Yue WS, Lau KK, Siu CW, Wang M, Yan GH, Yiu KH, Tse HF: Impact of glycemic control on circulating endothelial progenitor cells and arterial stiffness in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2011, 10:113.
• [47]Churdchomjan W, Kheolamai P, Manochantr S, Tapanadechopone P, Tantrawatpan C, U-pratya Y, Issaragrisil S: Comparison of endothelial progenitor cell function in type 2 diabetes with good and poor glycemic control. BMC Endocr Disord 2010, 10:5.
• [48]Estes ML, Mund JA, Mead LE, Prater DN, Cai S, Wang H, Pollok KE, Murphy MP, An CS, Srour EF, Ingram DA Jr, Case J: Application of polychromatic flow cytometry to identify novel subsets of circulating cells with angiogenic potential. Cytometry A 2010, 77(9):831-839.