title: DPP-4 inhibition has beneficial effects on the heart after myocardial infarction.
abstract: OBJECTIVE
  Dipeptidyl peptidase-4 (DPP-4) inhibitors are reported to have protective effects on various cells but it is unclear how DPP-4 inhibitors have cardioprotective effects. Our aim was to study the mechanisms of cardioprotective effects by DPP-4 inhibition.
  
  
  RESULTS
  C57BL/6 mice and DPP-4 knockout (DPP-4KO) mice were subjected to left coronary artery ligation to produce acute myocardial infarction (MI). C57BL/6 mice were then treated with vehicle or DPP-4 inhibitor. Left ventricular function, infarct size, the number of vessels, and myocardial ischemia were assessed at 5days after MI. The treatment with DPP-4 inhibitor significantly improved cardiac function and decreased the infarct size. DPP-4 inhibitor increased the ratio of endothelial cell numbers to a cardiomyocyte. The extent of myocardial ischemia and the number of TUNEL-positive cells in the border area were significantly decreased by DPP-4 inhibitor. Stromal cell-derived factor-1α (SDF-1α) level in myocardium was significantly increased by DPP-4 inhibitor. Those cardioprotective effects after MI were also recognized in DPP-4KO mice. DPP-4 protein was expressed on rat neonatal cardiomyocytes and DPP-4 inhibitor significantly reduced hypoxia-induced apoptosis in the cardiomyocytes. However, this effect was abolished by the pretreatment with a CXCR4 antagonist or a signal transducer and activator of transcription 3 (STAT3) inhibitor. The beneficial effects of DPP-4 inhibitor on heart failure after MI were abolished by cardiomyocyte-specific deletion of STAT3.
  
  
  CONCLUSIONS
  DPP-4 inhibition may have direct protective effects on the post-MI heart by inducing an antiapoptotic effect and inhibiting a decrease in vessel number through the SDF-1α/CXCR4-mediated STAT3 signaling pathway.
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kubota
authors.affiliation: Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan. Electronic address: htakano-cib@umin.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takano
authors.affiliation: Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Haixiu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Department of Bio-Medical Engineering, Tokai University, 317 Nishino, Numazu 410-0395, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tadokoro
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hirose
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kobara
authors.affiliation: Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamada-Inagawa
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000172:deficiency / Q000235:genetics*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: C514936:CXCR4 protein, mouse; D002316:Cardiotonic Agents; D054377:Chemokine CXCL12; D054873:Dipeptidyl-Peptidase IV Inhibitors; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D018819:Dipeptidyl Peptidase 4
keywords: Apoptosis; DPP-4; Heart failure; Myocardial infarction; STAT3