title: Short-term inhibition of DPP-4 enhances endothelial regeneration after acute arterial injury via enhanced recruitment of circulating progenitor cells.
abstract: BACKGROUND
  Endothelial injuries regularly occur in atherosclerosis and during interventional therapies of the arterial occlusive disease. Disturbances in the endothelial integrity can lead to insufficient blood supply and bear the risk of thrombus formation and acute vascular occlusion. At present, effective therapeutics to restore endothelial integrity are barely available. We analyzed the effect of pharmacological DPP-4-inhibition by Sitagliptin on endogenous progenitor cell-based endothelial regeneration via the SDF-1α/CXCR4-axis after acute endothelial damage in a mouse model of carotid injury.
  
  
  RESULTS
  Induction of a defined endothelial injury was performed in the carotid artery of C57Bl/6 mice which led to a local upregulation of SDF-1α expression. Animals were treated with placebo, Sitagliptin or Sitagliptin+AMD3100. Using mass spectrometry we could prove that Sitagliptin prevented cleavage of the chemokine SDF-1α. Accordingly, increased SDF-1α concentrations enhanced recruitment of systemically applied and endogenous circulating CXCR4+ progenitor cells to the site of vascular injury followed by a significantly accelerated reendothelialization as compared to placebo-treated animals. Improved endothelial recovery, as well as recruitment of circulating CXCR4+ progenitor cells (CD133+, Flk1+), was reversed by CXCR4-antagonization through AMD3100. In addition, short-term Sitagliptin treatment did not significantly promote neointimal or medial hyperplasia.
  
  
  CONCLUSIONS
  Sitagliptin can accelerate endothelial regeneration after acute endothelial injury. DPP-4 inhibitors prevent degradation of the chemokine SDF-1α and thus improve the recruitment of regenerative circulating CXCR4+ progenitor cells which mediate local endothelial cell proliferation without adversely affecting vessel wall architecture.
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany; Institute of Physiology, Cardiovascular Research, University of Zurich, Campus Irchel, Zurich, Switzerland; Department of Internal Medicine III, Medical University Innsbruck, Innsbruck, Austria. Electronic address: mail@med.cbrenner.net.
authors.forename: Christoph
authors.initials: C
authors.lastname: Brenner
authors.affiliation: Department of Cardiology, University Hospital Zurich, Zurich, Switzerland; Institute of Physiology, Cardiovascular Research, University of Zurich, Campus Irchel, Zurich, Switzerland.
authors.forename: Nicolle
authors.initials: N
authors.lastname: Kränkel
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kühlenthal
authors.affiliation: Institute of Molecular Biology, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Israel
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Remm
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Institute of Veterinary Pathology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Herbach
authors.affiliation: Institute of Physiology, Cardiovascular Research, University of Zurich, Campus Irchel, Zurich, Switzerland; Department of Internal Medicine IV, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Speer
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grabmaier
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Laskowski
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Gross
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Theiss
authors.affiliation: Institute of Veterinary Pathology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Wanke
authors.affiliation: Department of Cardiology, University Hospital Zurich, Zurich, Switzerland; Institute of Physiology, Cardiovascular Research, University of Zurich, Campus Irchel, Zurich, Switzerland.
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany; Department of Internal Medicine III, Medical University Innsbruck, Innsbruck, Austria. Electronic address: wolfgang-michael.franz@uki.at.
authors.forename: Wolfgang-Michael
authors.initials: WM
authors.lastname: Franz
mesh_terms: D000208:Acute Disease; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement; D049109:Cell Proliferation; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011719:Pyrazines / Q000494:pharmacology*; D012038:Regeneration; D015398:Signal Transduction; D000068900:Sitagliptin Phosphate; D013234:Stem Cells / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000068900:Sitagliptin Phosphate
keywords: Endothelial injury; Regeneration; SDF-1α/CXCR4; Sitagliptin