A decrease in the number and dysfunction of endothelial progenitor cells (EPC) may increase the risk for progression of cardiovascular disease (CVD) in type 1 diabetic patients with diabetic nephropathy (DN). Our aim was to evaluate EPC numbers in asymptomatic CVD type 1 diabetic patients with or without DN and to study the effect of CVD and medication on EPC numbers. Methods: We examined EPC numbers in 37 type 1 diabetic patients with DN and 35 type 1 diabetic patients with long-standing normoalbuminuria. Patients were without symptoms of CVD and the prevalence of CVD was previously shown to be very low. EPC number was assessed in in vitro cultures by fluorescent staining of attached cells. Results: There was no difference in EPC numbers between patients with DN (mean ± SD 120 ± 49 cells/field) and normoalbuminuria (108 ± 41 cells/field; p = 0.25). Furthermore, EPC number was not associated with CVD (p > 0.05). Conventional risk factors were significantly higher in patients with DN and they received more CVD-preventive treatment. All patients receiving simvastatin or calcium-channel blockers had higher numbers of EPC compared to patients not treated with these drugs. Conclusions: Asymptomatic patients with DN had EPC numbers similar to normoalbuminuric patients, which was related to aggressive CVD intervention therapy. This may have contributed to the low prevalence of CVD.

Keywords:
Cardiovascular disease, Diabetes mellitus, Diabetic nephropathy, Endothelial progenitor cells
1.
Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, Patel A, Cass A, Neal B, Poulter N, Mogensen CE, Cooper M, Marre M, Williams B, Hamet P, Mancia G, Woodward M, MacMahon S, Chalmers J: Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol 2009;20:1813–1821.
2.
Astrup AS, Tarnow L, Rossing P, Pietraszek L, Riis HP, Parving H-H: Improved prognosis in type 1 diabetic patients with nephropathy: a prospective follow-up study. Kidney Int 2005;68:1250–1257.
3.
Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM: Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999;85:221–228.
4.
Werner N, Nickenig G: Influence of cardiovascular risk factors on endothelial progenitor cells: limitations for therapy? Arterioscler Thromb Vasc Biol 2006;26:257–266.
5.
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;106:2781–2786.
6.
Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ: Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 2004;53:195–199.
7.
Fadini GP, de KS, Agostini C, Boscaro E, Tiengo A, Dimmeler S, Avogaro A: Low CD34+ cell count and metabolic syndrome synergistically increase the risk of adverse outcomes. Atherosclerosis 2009;207:213–219.
8.
Goligorsky MS, Chen J, Brodsky S: Workshop: endothelial cell dysfunction leading to diabetic nephropathy: focus on nitric oxide. Hypertension 2001;37:744–748.
9.
Bahlmann FH, deGroot K, Duckert T, Niemczyk E, Bahlmann E, Boehm SM, Haller H, Fliser D: Endothelial progenitor cell proliferation and differentiation is regulated by erythropoietin. Kidney Int 2003;64:1648–1652.
10.
Choi JH, Kim KL, Huh W, Kim B, Byun J, Suh W, Sung J, Jeon ES, Oh HY, Kim DK: Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure. Arterioscler Thromb Vasc Biol 2004;24:1246–1252.
11.
Walter DH, Rittig K, Bahlmann FH, Kirchmair R, Silver M, Murayama T, Nishimura H, Losordo DW, Asahara T, Isner JM: Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 2002;105:3017–3024.
12.
Kim WY, Astrup AS, Stuber M, Tarnow L, Falk E, Botnar RM, Simonsen C, Pietraszek L, Hansen PR, Manning WJ, Andersen NT, Parving H-H: Subclinical coronary and aortic atherosclerosis detected by magnetic resonance imaging in type 1 diabetes with and without diabetic nephropathy. Circulation 2007;115:228–235.
13.
Bahlmann FH, de GK, Mueller O, Hertel B, Haller H, Fliser D: Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension 2005;45:526–529.
14.
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:E1–E7.
15.
Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM, Dimmeler S: Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001;103:2885–2890.
16.
Min TQ, Zhu CJ, Xiang WX, Hui ZJ, Peng SY: Improvement in endothelial progenitor cells from peripheral blood by ramipril therapy in patients with stable coronary artery disease. Cardiovasc Drugs Ther 2004;18:203–209.
17.
Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM: HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001;108:391–397.
18.
Hu Z, Zhang F, Yang Z, Zhang J, Zhang D, Yang N, Zhang Y, Cao K: Low-dose aspirin promotes endothelial progenitor cell migration and adhesion and prevents senescence. Cell Biol Int 2008;32:761–768.
19.
Sugiura T, Kondo T, Kureishi-Bando Y, Numaguchi Y, Yoshida O, Dohi Y, Kimura G, Ueda R, Rabelink TJ, Murohara T: Nifedipine improves endothelial function: role of endothelial progenitor cells. Hypertension 2008;52:491–498.
20.
Fadini GP, Baesso I, Albiero M, Sartore S, Agostini C, Avogaro A: Technical notes on endothelial progenitor cells: ways to escape from the knowledge plateau. Atherosclerosis 2008;197:496–503.
21.
Reinhard H, Jacobsen PK, Lajer M, Pedersen N, Billestrup N, Mandrup-Poulsen T, Parving HH, Rossing P: Multifactorial treatment increases endothelial progenitor cells in patients with type 2 diabetes. Diabetologia 2010;53:2129–2133.
22.
Krzyzanowska K, Mittermayer F, Krugluger W, Schnack C, Hofer M, Wolzt M, Schernthaner G: Asymmetric dimethylarginine is associated with macrovascular disease and total homocysteine in patients with type 2 diabetes. Atherosclerosis 2006;189:236–240.
23.
Thum T, Tsikas D, Stein S, Schultheiss M, Eigenthaler M, Anker SD, Poole-Wilson PA, Ertl G, Bauersachs J: Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. J Am Coll Cardiol 2005;46:1693–1701.
24.
Makino H, Okada S, Nagumo A, Sugisawa T, Miyamoto Y, Kishimoto I, Kikuchi-Taura A, Soma T, Taguchi A, Yoshimasa Y: Decreased circulating CD34+ cells are associated with progression of diabetic nephropathy. Diabet Med 2009;26:171–173.
25.
Chade AR, Zhu X, Lavi R, Krier JD, Pislaru S, Simari RD, Napoli C, Lerman A, Lerman LO: Endothelial progenitor cells restore renal function in chronic experimental renovascular disease. Circulation 2009;119:547–557.
26.
Ikarashi K, Li B, Suwa M, Kawamura K, Morioka T, Yao J, Khan F, Uchiyama M, Oite T: Bone marrow cells contribute to regeneration of damaged glomerular endothelial cells. Kidney Int 2005;67:1925–1933.
27.
Sorrentino SA, Bahlmann FH, Besler C, Muller M, Schulz S, Kirchhoff N, Doerries C, Horvath T, Limbourg A, Limbourg F, Fliser D, Haller H, Drexler H, Landmesser U: Oxidant stress impairs in vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus: restoration by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 2007;116:163–173.
28.
Sibal L, Aldibbiat A, Agarwal SC, Mitchell G, Oates C, Razvi S, Weaver JU, Shaw JA, Home PD: Circulating endothelial progenitor cells, endothelial function, carotid intima-media thickness and circulating markers of endothelial dysfunction in people with type 1 diabetes without macrovascular disease or microalbuminuria. Diabetologia 2009;52:1464–1473.
29.
Deanfield JE, Halcox JP, Rabelink TJ: Endothelial function and dysfunction: testing and clinical relevance. Circulation 2007;115:1285–1295.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.