title: Left ventricular diastolic dysfunction and myocardial stiffness in diabetic mice is attenuated by inhibition of dipeptidyl peptidase 4.
abstract: OBJECTIVE
  Obesity and Type 2 diabetes mellitus (DM) induce left ventricular (LV) diastolic dysfunction, which contributes to an increasing prevalence of heart failure with a preserved LV ejection fraction. We investigated the effects of sitagliptin (SITA), an inhibitor of dipeptidylpeptidase-4 (DPP-4) and anti-diabetic drug, on LV structure and function of obese mice with Type 2 DM.
  
  
  RESULTS
  Obese Type 2 diabetic mice (Lepr(db/db), BKS.Cg-Dock7(m)+/+ Lepr(db)/J), displaying increased cardiomyocyte and LV stiffness at the age of 16 weeks, were treated with SITA (300 mg/kg/day) or vehicle for 8 weeks. SITA severely impaired serum DPP-4 activity, but had no effect on glycaemia. Invasive haemodynamic recordings showed that SITA reduced LV passive stiffness and increased LV stroke volume; LV end-systolic elastance remained unchanged. In addition, SITA reduced resting tension of isolated single cardiomyocytes and intensified phosphorylation of the sarcomeric protein titin. SITA also increased LV concentrations of cGMP and increased activity of protein kinase G (PKG). In vitro activation of PKG decreased resting tension of cardiomyocytes from vehicle-treated mice, but had no effect on resting tension of cardiomyocytes from SITA-treated mice.
  
  
  CONCLUSIONS
  In obese Type 2 diabetic mice, in the absence of hypoglycaemic effects, inhibition of DPP-4 decreases LV passive stiffness and improves global LV performance. These effects seem at least partially mediated by stimulatory effects on the myocardial cGMP-PKG pathway and, hence, on the phosphorylation status of titin and the hereto coupled cardiomyocyte stiffness modulus.
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, Amsterdam, the Netherlands Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University, Bochum, Germany.
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.affiliation: Laboratory of Physiopharmacology (Building T2), University of Antwerp, Universiteitsplein 1, Antwerp 2610, Belgium.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Hervent
authors.affiliation: Laboratory of Physiopharmacology (Building T2), University of Antwerp, Universiteitsplein 1, Antwerp 2610, Belgium.
authors.forename: Leni
authors.initials: L
authors.lastname: Vandekerckhove
authors.affiliation: Laboratoy of Medical Biochemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Matheeussen
authors.affiliation: Laboratory of Physiopharmacology (Building T2), University of Antwerp, Universiteitsplein 1, Antwerp 2610, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Demolder
authors.affiliation: Laboratoy of Medical Biochemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Lesley
authors.initials: L
authors.lastname: Baerts
authors.affiliation: Laboratoy of Medical Biochemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.affiliation: Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University, Bochum, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
authors.affiliation: Laboratory of Physiopharmacology (Building T2), University of Antwerp, Universiteitsplein 1, Antwerp 2610, Belgium gilles.dekeulenaer@ua.ac.be.
authors.forename: Gilles W
authors.initials: GW
authors.lastname: De Keulenaer
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D003187:Compliance / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003971:Diastole / Q000187:drug effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects; D011719:Pyrazines / Q000627:therapeutic use*; D011897:Random Allocation; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D009320:Atrial Natriuretic Factor; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D000068900:Sitagliptin Phosphate
keywords: Diabetes; Haemodynamics; Heart failure