Inhibition of Dipeptidyl Peptidase-4 Impairs Ventricular Function and Promotes Cardiac Fibrosis in High Fat-Fed Diabetic Mice

Diabetes. 2016 Mar;65(3):742-54. doi: 10.2337/db15-1224. Epub 2015 Dec 15.


Dipeptidyl peptidase-4 (DPP4) inhibitors used for the treatment of type 2 diabetes are cardioprotective in preclinical studies; however, some cardiovascular outcome studies revealed increased hospitalization rates for heart failure (HF) among a subset of DPP4 inhibitor-treated subjects with diabetes. We evaluated cardiovascular function in young euglycemic Dpp4(-/-) mice and in older, high fat-fed, diabetic C57BL/6J mice treated with either the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide or the highly selective DPP4 inhibitor MK-0626. We assessed glucose metabolism, ventricular function and remodeling, and cardiac gene expression profiles linked to inflammation and fibrosis after transverse aortic constriction (TAC) surgery, a pressure-volume overload model of HF. Young euglycemic Dpp4(-/-) mice exhibited a cardioprotective response after TAC surgery or doxorubicin administration, with reduced fibrosis; however, cardiac mRNA analysis revealed increased expression of inflammation-related transcripts. Older, diabetic, high fat-fed mice treated with the GLP-1R agonist liraglutide exhibited preservation of cardiac function. In contrast, diabetic mice treated with MK-0626 exhibited modest cardiac hypertrophy, impairment of cardiac function, and dysregulated expression of genes and proteins controlling inflammation and cardiac fibrosis. These findings provide a model for the analysis of mechanisms linking fibrosis, inflammation, and impaired ventricular function to DPP4 inhibition in preclinical studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly
  • Cytokines / drug effects
  • Cytokines / metabolism
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / metabolism
  • Diet, High-Fat
  • Dipeptidyl Peptidase 4 / genetics*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Fibrosis / genetics
  • Heart / drug effects
  • Heart Failure / genetics*
  • Heart Failure / metabolism
  • Hypoglycemic Agents / pharmacology
  • Immunoblotting
  • Inflammation
  • Liraglutide / pharmacology
  • Mice
  • Mice, Knockout
  • Myocardium / pathology*
  • RNA, Messenger / drug effects*
  • RNA, Messenger / metabolism
  • Transcriptome
  • Triazoles / pharmacology
  • Ventricular Function / drug effects*
  • Ventricular Function / genetics
  • Ventricular Remodeling / drug effects*
  • Ventricular Remodeling / genetics


  • Cytokines
  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • MK0626
  • RNA, Messenger
  • Triazoles
  • Liraglutide
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse