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

• Published in: Diabetes (New York, N.Y.) Vol. 65; no. 3; pp. 742 - 754
• Main Authors: Mulvihill, Erin E., Varin, Elodie M., Ussher, John R., Campbell, Jonathan E., Bang, K.W. Annie, Abdullah, Tahmid, Baggio, Laurie L., Drucker, Daniel J.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.03.2016
• Subjects: Animals; Cardiomegaly; Cytokines - drug effects; Cytokines - metabolism; Diabetes; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diet, High-Fat; Dipeptidyl Peptidase 4 - genetics; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Fibrosis - genetics; Genes; Heart - drug effects; Heart failure; Heart Failure - genetics; Heart Failure - metabolism; Hypoglycemic Agents - pharmacology; Immunoblotting; Inflammation; Liraglutide - pharmacology; Mice; Mice, Knockout; Myocardium - pathology; Peptides; Proteins; Ribonucleic acid; RNA; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Transcriptome; Triazoles - pharmacology; Ventricular Function - drug effects; Ventricular Function - genetics; Ventricular Remodeling - drug effects; Ventricular Remodeling - genetics
• DOI: 10.2337/db15-1224
• ISSN: 0012-1797; 1939-327X

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.