Publication
Title
Left ventricular diastolic dysfunction and myocardial stiffness in diabetic mice is attenuated by inhibition of dipeptidyl peptidase 4
Author
Abstract
Aims 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. Methods and results Obese Type 2 diabetic mice (Lepr(db/db), BKS. Cg-Dock(7m) +/+ 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.
Language
English
Source (journal)
Cardiovascular research. - London
Publication
London : 2014
ISSN
0008-6363
Volume/pages
104:3(2014), p. 423-431
ISI
000345836500005
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
[E?say:metaLocaldata.cgzprojectinf]
MEDIA - The metabolic road to diastolic heart failure.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 13.01.2015
Last edited 05.09.2017
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