title: Dipeptidyl peptidase-4 inhibitors and GLP-1 reduce myocardial infarct size in a glucose-dependent manner.
abstract: BACKGROUND
  The dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin and Vildagliptin lower blood glucose by augmenting endogenous levels of glucagon-like peptide-1 (GLP-1), an incretin which also confers cardioprotection. As such, we hypothesized that treatment with DPP-4 inhibitors are also cardioprotective.
  
  
  METHODS
  In ex vivo experiments: Male Sprague-Dawley rats were randomized to receive by oral gavage either Vildagliptin (20 mg/kg/day), Sitagliptin (100 mg/kg/day), or water for 2 weeks. Excised hearts were Langendorff-perfused with buffer containing either 5 mmol/L or 11 mmol/L glucose and subjected to 35 minutes ischaemia/120 minutes reperfusion. In in vivo experiments: Male young Wistar and Sprague-Dawley rats, middle aged Wistar and Goto-Kakizaki diabetic rats were randomized to receive by oral gavage either Sitagliptin (100 mg/kg/day), or water for 2 weeks. Rats were then subjected to 30 minutes ischaemia/120 minutes reperfusion and infarct size ascertained.
  
  
  RESULTS
  Two weeks pre-treatment with either Vildagliptin or Sitagliptin reduced ex vivo myocardial infarction (MI) size in hearts perfused with buffer containing 11 mmol/L glucose but not 5 mmol/L glucose. This effect was abolished by Exendin 9-39 (GLP-1 receptor antagonist) and H-89 (PKA antagonist). Treatment of perfused hearts with native GLP-1 was also glucose-sensitive, reducing MI size, at glucose concentrations 7, 9, and 11 mmol/L but not at 5 mmol/L. Finally, Sitagliptin reduced in vivo MI size in middle aged Wistar (7-8 mmol/L glucose) and Goto-Kakizaki (9-10 mmol/L glucose) rats where blood glucose was elevated, but not in young Wistar (5 mmol/L glucose) or Sprague-Dawley (5 mmol/L glucose) rats, where blood glucose was normal.
  
  
  CONCLUSIONS
  We find that chronic treatment with DPP-4 inhibitors reduced MI size, via the GLP-1 receptor-PKA pathway, in a glucose-dependent manner. Glucose-sensitive cardioprotection of endogenous GLP-1 in diabetic patients may in part explain why intensive control of serum glucose levels has been associated with increased cardiovascular risk.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hausenloy
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Whittington
authors.forename: Abigail M
authors.initials: AM
authors.lastname: Wynne
authors.forename: Shah S
authors.initials: SS
authors.lastname: Begum
authors.forename: Louise
authors.initials: L
authors.lastname: Theodorou
authors.forename: Niels
authors.initials: N
authors.lastname: Riksen
authors.forename: Mihaela M
authors.initials: MM
authors.lastname: Mocanu
authors.affiliation: The Hatter Cardiovascular Institute, UCL Institute of Cardiovascular Science and NIHR University College London Hospitals Biomedical Research Centre, 67 Chenies Mews, London WC1E 6HX, UK. d.yellon@ucl.ac.uk.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000187:drug effects* / Q000502:physiology; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors; D012720:Severity of Illness Index; D015398:Signal Transduction; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D009570:Nitriles; D011719:Pyrazines; D011759:Pyrrolidines; D018027:Receptors, Glucagon; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D017868:Cyclic AMP-Dependent Protein Kinases; D000077597:Vildagliptin; D005947:Glucose; D000218:Adamantane; D000068900:Sitagliptin Phosphate