title: Dipeptidyl peptidase inhibition prevents diastolic dysfunction and reduces myocardial fibrosis in a mouse model of Western diet induced obesity.
abstract: OBJECTIVE
  Consumption of a high-fat/high-fructose Western diet (WD) is linked to rising obesity and heart disease, particularly diastolic dysfunction which characterizes early obesity/metabolic cardiomyopathy. Mounting evidence supports a role for inflammation, oxidative stress and fibrosis in the pathophysiology of metabolic cardiomyopathy. Dipeptidyl peptidase-4 (DPP-4) is a circulating exopeptidase recently reported to be elevated in the plasma of patients with insulin resistance (IR), obesity and heart failure. We hypothesized that a model of WD induced obesity/metabolic cardiomyopathy would exhibit increased DPP-4 activity and cardiac fibrosis with DPP-4 inhibition preventing cardiac fibrosis and the associated diastolic dysfunction.
  
  
  METHODS
  Four-week-old C57BL6/J mice were fed a high-fat/high-fructose WD with the DPP-4 inhibitor MK0626 for 16 weeks. Cardiac function was examined by high-resolution cine-cardiac magnetic resonance imaging (MRI). Phenotypic analysis included measurements of body and heart weight, systemic IR and DPP-4 activity. Immunohistochemistry and transmission electron microscopy (TEM) were utilized to identify underlying pathologic mechanisms.
  
  
  RESULTS
  We found that chronic WD consumption caused obesity, IR, elevated plasma DPP-4 activity, heart enlargement and diastolic dysfunction. DPP-4 inhibition with MK0626 in WD fed mice resulted in >75% reduction in plasma DPP-4 activity, improved IR and normalized diastolic relaxation. WD consumption induced myocardial oxidant stress and fibrosis with amelioration by MK0626. TEM of hearts from WD fed mice revealed abnormal mitochondrial and perivascular ultrastructure partially corrected by MK0626.
  
  
  CONCLUSIONS
  This study provides evidence of a role for increased DPP-4 activity in metabolic cardiomyopathy and a potential role for DPP-4 inhibition in prevention and/or correction of oxidant stress/fibrosis and associated diastolic dysfunction.
authors.affiliation: Division of Cardiovascular Medicine, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA; Department of Medicine, University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans Hospital, Columbia MO, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Bostick
authors.affiliation: Department of Medicine, University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans Hospital, Columbia MO, USA; Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA.
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.affiliation: Harry S. Truman Memorial Veterans Hospital, Columbia MO, USA; Department of Radiology, University of Missouri, Columbia, MO, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Medicine, University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans Hospital, Columbia MO, USA; Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA.
authors.forename: Annayya
authors.initials: A
authors.lastname: Aroor
authors.affiliation: Department of Medicine, University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans Hospital, Columbia MO, USA; Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Rehmer
authors.affiliation: Department of Medicine, University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans Hospital, Columbia MO, USA; Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA.
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Department of Medicine, University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans Hospital, Columbia MO, USA; Division of Endocrinology and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA. Electronic address: sowersj@health.missouri.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000517:prevention & control*; D003971:Diastole / Q000187:drug effects*; D004032:Diet; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009765:Obesity / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C570834:MK0626; D014230:Triazoles
keywords: DPP-4; Heart failure; Inflammation; Oxidative stress