The dipeptidyl peptidase-4 inhibitor Saxagliptin improves function of circulating pro-angiogenic cells from type 2 diabetic patients

Cardiovascular Diabetology

Gian Paolo Fadini²  Angelo Avogaro²  Roberta Cappellari¹  Lisa Menegazzo²  Mattia Albiero¹  Nicol Poncina² 

[1] Venetian Institute of Molecular Medicine, University Hospital of Padova, Via Giustiniani, Padova 2. 35100, Italy;Department of Medicine, Division of Metabolic Diseases, University Hospital of Padova, Via Giustiniani, Padova 2. 35100, Italy

关键词: Cardiovascular disease;    Angiogenesis;    Stem cells;    Regeneration;   

Others  :  792970
DOI  :  10.1186/1475-2840-13-92

 received in 2014-02-18, accepted in 2014-05-09,  发布年份 2014

【 摘 要 】

Background

Type 2 diabetes (T2D) is associated with reduction and dysfunction of circulating pro-angiogenic cells (PACs). DPP-4 inhibitors, a class of oral agents for T2D, might possess pleiotropic vasculoprotective activities. Herein, we tested whether DPP-4 inhibition with Saxagliptin affects the function of circulating PACs from T2D and healthy subjects.

Methods

PACs were isolated from T2D (n = 20) and healthy (n = 20) subjects. Gene expression, clonogenesis, proliferation, adhesion, migration and tubulisation were assessed in vitro by incubating PACs with or without Saxagliptin and SDF-1α. Stimulation of angiogenesis by circulating cells from T2D patients treated with Saxagliptin or other non-incretinergic drugs was assessed in vivo using animal models.

Results

Soluble DPP-4 activity was predominant over cellular activity and was successfully inhibited by Saxagliptin. At baseline, T2D compared to healthy PACs contained less acLDL⁺Lectin⁺ cells, and showed altered expression of genes related to adhesion and cell cycle regulation. This was reflected by impaired adhesion and clonogenesis/proliferative response of T2D PACs. Saxagliptin + SDF-1α improved adhesion and tube sustaining capacity of PACs from T2D patients. CD14⁺ PACs were more responsive to Saxagliptin than CD14^- PACs. While Saxagliptin modestly reduced angiogenesis by mature endothelial cells, circulating PACs-progeny cells from T2D patients on Saxagliptin treatment displayed higher growth factor-inducible in vivo angiogenetic activity, compared to cells from T2D patients on non-incretinergic regimen.

Conclusions

Saxagliptin reverses PACs dysfunction associated with T2D in vitro and improves inducible angiogenesis by circulating cells in vivo. These data add knowledge to the potential pleiotropic cardiovascular effects of DPP-4 inhibition.

【 授权许可】

   
2014 Poncina et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Avogaro A, Albiero M, Menegazzo L, de Kreutzenberg S, Fadini GP: Endothelial dysfunction in diabetes: the role of reparatory mechanisms. Diabetes Care 2011, 34(Suppl 2):S285-S290.
• [2]Fadini GP: A reappraisal of the role of circulating (progenitor) cells in the pathobiology of diabetic complications. Diabetologia 2014, 57(1):4-15.
• [3]Fadini GP, Sartore S, Albiero M, Baesso I, Murphy E, Menegolo M, Grego F, Vigili de Kreutzenberg S, Tiengo A, Agostini C, Avogaro A: Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol 2006, 26(9):2140-2146.
• [4]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. BioMed Central Full Text
• [5]Keats EC, Khan ZA: Vascular stem cells in diabetic complications: evidence for a role in the pathogenesis and the therapeutic promise. Cardiovasc Diabetol 2012, 11:37. BioMed Central Full Text
• [6]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. BioMed Central Full Text
• [7]Fadini GP, Albiero M, Vigili de Kreutzenberg S, Boscaro E, Cappellari R, Marescotti M, Poncina N, Agostini C, Avogaro A: Diabetes impairs stem cell and proangiogenic cell mobilization in humans. Diabetes Care 2013, 36(4):943-949.
• [8]Menegazzo L, Albiero M, Avogaro A, Fadini GP: Endothelial progenitor cells in diabetes mellitus. Biofactors 2012, 38(3):194-202.
• [9]Fadini GP, Avogaro A: Potential manipulation of endothelial progenitor cells in diabetes and its complications. Diabetes Obes Metab 2010, 12(7):570-583.
• [10]Fadini GP, Losordo D, Dimmeler S: Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res 2012, 110(4):624-637.
• [11]Ussher JR, Drucker DJ: Cardiovascular biology of the incretin system. Endocr Rev 2012, 33(2):187-215.
• [12]Fadini GP, Avogaro A: Cardiovascular effects of DPP-4 inhibition: beyond GLP-1. Vascul Pharmacol 2011, 55(1–3):10-16.
• [13]Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC: Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004, 10(8):858-864.
• [14]Zheng H, Fu G, Dai T, Huang H: Migration of endothelial progenitor cells mediated by stromal cell-derived factor-1alpha/CXCR4 via PI3K/Akt/eNOS signal transduction pathway. J Cardiovasc Pharmacol 2007, 50(3):274-280.
• [15]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.
• [16]Huang CY, Shih CM, Tsao NW, Lin YW, Huang PH, Wu SC, Lee AW, Kao YT, Chang NC, Nakagami H, Morishita R, Ou KL, Hou WC, Lin CY, Shyu KG, Lin FY: Dipeptidyl peptidase-4 inhibitor improves neovascularization by increasing circulating endothelial progenitor cells. Br J Pharmacol 2012, 167(7):1506-1519.
• [17]Shih CM, Chen YH, Lin YW, Tsao NW, Wu SC, Kao YT, Chiang KH, Li CY, Chang NC, Lin CY, Huang CY, Lin FY: MK-0626, A Dipeptidyl Peptidase-4 Inhibitor, Improves Neovascularization by Increasing Both the Number of Circulating Endothelial Progenitor Cells and Endothelial Nitric Oxide Synthetase Expression. Curr Med Chem 2014, 21(17):2012-2022.
• [18]Hur J, Yang HM, Yoon CH, Lee CS, Park KW, Kim JH, Kim TY, Kim JY, Kang HJ, Chae IH, Oh BH, Park YB, Kim HS: Identification of a novel role of T cells in postnatal vasculogenesis: characterization of endothelial progenitor cell colonies. Circulation 2007, 116(15):1671-1682.
• [19]Chen X: Biochemical properties of recombinant prolyl dipeptidases DPP-IV and DPP8. Adv Exp Med Biol 2006, 575:27-32.
• [20]Fadini GP, Albiero M, Seeger F, Poncina N, Menegazzo L, Angelini A, Castellani C, Thiene G, Agostini C, Cappellari R, Boscaro E, Zeiher A, Dimmeler S, Avogaro A: Stem cell compartmentalization in diabetes and high cardiovascular risk reveals the role of DPP-4 in diabetic stem cell mobilopathy. Basic Res Cardiol 2013, 108(1):313.
• [21]Fadini GP, Albiero M, Menegazzo L, de Kreutzenberg SV, Avogaro A: The increased dipeptidyl peptidase-4 activity is not counteracted by optimized glucose control in type 2 diabetes, but is lower in metformin-treated patients. Diabetes Obes Metab 2012, 14(6):518-522.
• [22]Broxmeyer HE, Hoggatt J, O'Leary HA, Mantel C, Chitteti BR, Cooper S, Messina-Graham S, Hangoc G, Farag S, Rohrabaugh SL, Ou X, Speth J, Pelus LM, Srour EF, Campbell TB: Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat Med 2012, 18(12):1786-1796.
• [23]Spinetti G, Fortunato O, Cordella D, Portararo P, Krankel N, Katare R, Sala-Newby GB, Richer C, Vincent MP, Alhenc-Gelas F, Tonolo G, Cherchi S, Emanueli C, Madeddu P: Tissue kallikrein is essential for invasive capacity of circulating proangiogenic cells. Circ Res 2011, 108(3):284-293.
• [24]Wara AK, Croce K, Foo S, Sun X, Icli B, Tesmenitsky Y, Esen F, Rosenzweig A, Feinberg MW: Bone marrow-derived CMPs and GMPs represent highly functional proangiogenic cells: implications for ischemic cardiovascular disease. Blood 2011, 118(24):6461-6464.
• [25]Leistner DM, Fischer-Rasokat U, Honold J, Seeger FH, Schachinger V, Lehmann R, Martin H, Burck I, Urbich C, Dimmeler S, Zeiher AM, Assmus B: Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI): final 5-year results suggest long-term safety and efficacy. Clin Res Cardiol 2011, 100(10):925-934.
• [26]Lancrin C, Sroczynska P, Stephenson C, Allen T, Kouskoff V, Lacaud G: The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature 2009, 457(7231):892-895.
• [27]Ohtani K, Vlachojannis GJ, Koyanagi M, Boeckel JN, Urbich C, Farcas R, Bonig H, Marquez VE, Zeiher AM, Dimmeler S: Epigenetic regulation of endothelial lineage committed genes in pro-angiogenic hematopoietic and endothelial progenitor cells. Circ Res 2011, 109(11):1219-1229.
• [28]Spinetti G, Fortunato O, Caporali A, Shantikumar S, Marchetti M, Meloni M, Descamps B, Floris I, Sangalli E, Vono R, Faglia E, Specchia C, Pintus G, Madeddu P, Emanueli C: MicroRNA-15a and microRNA-16 impair human circulating proangiogenic cell functions and are increased in the proangiogenic cells and serum of patients with critical limb ischemia. Circ Res 2013, 112(2):335-346.
• [29]Chen YH, Lin SJ, Lin FY, Wu TC, Tsao CR, Huang PH, Liu PL, Chen YL, Chen JW: High glucose impairs early and late endothelial progenitor cells by modifying nitric oxide-related but not oxidative stress-mediated mechanisms. Diabetes 2007, 56(6):1559-1568.
• [30]Ho JC, Lai WH, Li MF, Au KW, Yip MC, Wong NL, Ng ES, Lam FF, Siu CW, Tse HF: Reversal of endothelial progenitor cell dysfunction in patients with type 2 diabetes using a conditioned medium of human embryonic stem cell-derived endothelial cells. Diabetes Metab Res Rev 2012, 28(5):462-473.
• [31]Fadini GP, Avogaro A: Dipeptidyl peptidase-4 inhibition and vascular repair by mobilization of endogenous stem cells in diabetes and beyond. Atherosclerosis 2013, 229(1):23-29.
• [32]Fiorina P, Pietramaggiori G, Scherer SS, Jurewicz M, Mathews JC, Vergani A, Thomas G, Orsenigo E, Staudacher C, La Rosa S, Capella C, Carothers A, Zerwes HG, Luzi L, Abdi R, Orgill DP: The mobilization and effect of endogenous bone marrow progenitor cells in diabetic wound healing. Cell Transplant 2010, 19(11):1369-1381.
• [33]Marfella R, Sasso FC, Rizzo MR, Paolisso P, Barbieri M, Padovano V, Carbonara O, Gualdiero P, Petronella P, Ferraraccio F, Petrella A, Canonico R, Campitiello F, Della Corte A, Paolisso G, Canonico S: Dipeptidyl peptidase 4 inhibition may facilitate healing of chronic foot ulcers in patients with type 2 diabetes. Exp Diabetes Res 2012, 2012:892706.
• [34]Goncalves A, Leal E, Paiva A, Teixeira Lemos E, Teixeira F, Ribeiro CF, Reis F, Ambrosio AF, Fernandes R: Protective effects of the dipeptidyl peptidase IV inhibitor sitagliptin in the blood-retinal barrier in a type 2 diabetes animal model. Diabetes Obes Metab 2012, 14(5):454-463.
• [35]Cobble ME, Frederich R: Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data. Cardiovasc Diabetol 2012, 11:6. BioMed Central Full Text
• [36]Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I: Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013, 369(14):1317-1326.
• [37]Petrelli A, Maestroni A, Fadini GP, Belloni D, Venturini M, Albiero M, Kleffel S, Mfarrej BG, Maschio AD, Maffi P, Avogaro A, Ferrero E, Zerbini G, Secchi A, Fiorina P: Improved function of circulating angiogenic cells is evident in type 1 diabetic islet-transplanted patients. Am J Transplant 2010, 10(12):2690-2700.
• [38]Petrelli A, Di Fenza R, Carvello M, Gatti F, Secchi A, Fiorina P: Strategies to reverse endothelial progenitor cell dysfunction in diabetes. Exp Diabetes Res 2012, 2012:471823.