title: DPP-4 inhibition ameliorates atherosclerosis by priming monocytes into M2 macrophages.
abstract: OBJECTIVE
  Glipitins are widely used for the treatment of type 2 diabetic patients. In addition to their improvement of glycemic control, animal studies have suggested an independent anti-atherosclerotic effect of gliptins. Nevertheless, recent clinical trials regarding long-term effects of gliptin therapy on vascular events have been disappointing. This discrepancy led us to better dissect the functional role of SDF-1/CXCR4 signaling as a potential mechanism underlying gliptin action. The study should give improved understanding of the potential of gliptin therapy in the prevention and treatment of atherosclerosis.
  
  
  RESULTS
  In an ApoE-/- mouse model on high cholesterol diet, long-term treatment with the DPP-4 inhibitor Sitagliptin significantly reduced atherosclerosic plaque load in the aorta. Flow cytometry analyses showed an enrichment of M2 macrophages in the aortic wall under gliptin therapy. Importantly, the number of recruited CD206+ macrophages was inversely correlated with total plaque area while no correlation was found for the overall macrophage population or M1 macrophages. Blockade of CXCR4/SDF-1 signaling by AMD3100 inhibited aortic M2 accumulation and the therapeutic effect of Sitagliptin. Correspondingly, Sitagliptin shifted the polarization profile of macrophages towards a M2-like phenotype.
  
  
  CONCLUSIONS
  Sitagliptin-mediated inhibition of early atherosclerosis is based on M2-polarization during monocyte differentiation via the SDF-1/CXCR4 signaling. In contrast to earlier assumptions gliptin treatment might be especially effective in prevention of atherosclerosis.
authors.affiliation: Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, University of Munich, Munich, Germany. Electronic address: mail@med.cbrenner.net.
authors.forename: C
authors.initials: C
authors.lastname: Brenner
authors.affiliation: Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: W M
authors.initials: WM
authors.lastname: Franz
authors.affiliation: Department of Internal Medicine I, University of Munich, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kühlenthal
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland; Department of Cardiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Kuschnerus
authors.affiliation: Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, University of Munich, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Remm
authors.affiliation: Department of Internal Medicine I, University of Munich, Munich, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Gross
authors.affiliation: Department of Internal Medicine I, University of Munich, Munich, Germany.
authors.forename: H D
authors.initials: HD
authors.lastname: Theiss
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland; Department of Cardiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Landmesser
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland; Department of Cardiology, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: nicolle.kraenkel@charite.de.
authors.forename: N
authors.initials: N
authors.lastname: Kränkel
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000517:prevention & control; D054377:Chemokine CXCL12 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005434:Flow Cytometry / Q000379:methods; D006937:Hypercholesterolemia / Q000188:drug therapy; D054795:Incretins / Q000097:blood / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy; D019718:Receptors, CXCR4 / Q000235:genetics; D060865:Repetition Priming / Q000502:physiology*; D000068900:Sitagliptin Phosphate / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D001057:Apolipoproteins E; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D054873:Dipeptidyl-Peptidase IV Inhibitors; D054795:Incretins; D019718:Receptors, CXCR4; D000068900:Sitagliptin Phosphate
keywords: Atherosclerosis; M2 macrophages; Priming; SDF-1; Sitagliptin