title: Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats.
abstract: BACKGROUND
  Type 2 diabetes mellitus (T2DM) worsens the outcome after myocardial infarction (MI). Here, we hypothesized that inhibition of dipeptidyl peptidase-4 (DPP-4) improves survival after MI in T2DM by modifying autophagy in the non-infarcted region of the heart.
  
  
  RESULTS
  Under baseline conditions, there was no significant difference between levels of myocardial autophagy marker proteins in OLETF, a rat model of T2DM, and in LETO, a non-diabetic control. However, in contrast to the response in LETO, LC3-II protein and LC3-positive autophagosomes in the non-infarcted region of the myocardium were not increased after MI in OLETF. The altered autophagic response in OLETF was associated with lack of AMPK/ULK-1 activation, attenuated response of Akt/mTOR/S6 signaling and increased Beclin-1-Bcl-2 interaction after MI. Treatment with vildagliptin (10 mg/kg/day s.c.), a DPP-4 inhibitor, suppressed Beclin-1-Bcl-2 interaction and increased both LC3-II protein level and autophagosomes in the non-infarcted region in OLETF, though it did not normalize AMPK/ULK-1 or mTOR/S6 signaling. Plasma insulin level, but not glucose level, was significantly reduced by vildagliptin at the dose used in this study. Survival rate at 48 h after MI was significantly lower in OLETF than in LETO (32 vs. 82%), despite similar infarct sizes. Vildagliptin improved the survival rate in OLETF to 80%, the benefit of which was abrogated by chloroquine, an autophagy inhibitor.
  
  
  CONCLUSIONS
  The results indicate that vildagliptin reduces T2DM-induced increase in post-MI acute mortality possibly by restoring the autophagic response through attenuation of Bcl-2-Beclin-1 interaction.
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. michi_seramu_9754@yahoo.co.jp.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Murase
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. kuno@sapmed.ac.jp.|Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, 060-8543, Japan. kuno@sapmed.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuno
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. tmiki@sapmed.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Miki
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. tannnom@sapmed.ac.jp.
authors.forename: Masaya
authors.initials: M
authors.lastname: Tanno
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. tyano@sapmed.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yano
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. kouzu@sapmed.ac.jp.
authors.forename: Hidemichi
authors.initials: H
authors.lastname: Kouzu
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. ishikawas@sapmed.ac.jp.
authors.forename: Satoko
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. tobisawadesu@yahoo.co.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tobisawa
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. ogasawara13202831@yahoo.co.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ogasawara
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. nishizawa_1114@sapmed.ac.jp.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Nishizawa
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. miura@sapmed.ac.jp.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002738:Chloroquine / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D007279:Injections, Subcutaneous; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D020334:Rats, Inbred OLETF; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D000077597:Vildagliptin
chemical_list: D000218:Adamantane; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D002738:Chloroquine; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D008869:Microtubule-Associated Proteins; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines; D000077597:Vildagliptin; C512829:Becn1 protein, rat; C526109:Anxa3 protein, rat; C000602659:DPP4 protein, rat