title: Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure.
abstract: BACKGROUND
  Progressive remodeling after myocardial infarction (MI) is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), an enzyme which inhibits GLP-1 activity. We hypothesized that the DPP-4 inhibitor vildagliptin will increase levels of GLP-1 and may exert protective effects on cardiac function after MI.
  
  
  METHODS
  Sprague-Dawley rats were either subjected to coronary ligation to induce MI and left ventricular (LV) remodeling, or sham operation. Parts of the rats with an MI were pre-treated for 2 days with the DPP-4 inhibitor vildagliptin (MI-Vildagliptin immediate, MI-VI, 15 mg/kg/day). The remainder of the rats was, three weeks after coronary artery ligation, subjected to treatment with DPP-4 inhibitor vildagliptin (MI-Vildagliptin Late, MI-VL) or control (MI). At 12 weeks, echocardiography and invasive hemodynamics were measured and molecular analysis and immunohistochemistry were performed.
  
  
  RESULTS
  Vildagliptin inhibited the DPP-4 enzymatic activity by almost 70% and increased active GLP-1 levels by about 3-fold in plasma in both treated groups (p < 0.05 vs. non-treated groups). Cardiac function (ejection fraction) was decreased in all 3 MI groups compared with Sham group (p < 0.05); treatment with vildagliptin, either early or late, did not reverse cardiac remodeling. ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide) mRNA levels were significantly increased in all 3 MI groups, but no significant reductions were observed in both vildagliptin groups. Vildagliptin also did not change cardiomyocyte size or capillary density after MI. No effects were detected on glucose level and body weight in the post-MI remodeling model.
  
  
  CONCLUSIONS
  Vildagliptin increases the active GLP-1 level via inhibition of DPP-4, but it has no substantial protective effects on cardiac function in this well established long-term post-MI cardiac remodeling model.
authors.affiliation: University Medical Center Groningen, University of Groningen, Department of Cardiology, Groningen, The Netherlands.
authors.forename: Meimei
authors.initials: M
authors.lastname: Yin
authors.forename: Herman H W
authors.initials: HH
authors.lastname: Silljé
authors.forename: Maxi
authors.initials: M
authors.lastname: Meissner
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology; D009570:Nitriles / Q000008:administration & dosage*; D011759:Pyrrolidines / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane