Dipeptidyl Peptidase-4 (DPP4) inhibitors used for the treatment of Type 2 diabetes mellitus (T2DM) 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 diabetic subjects. 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 following transverse aortic constriction (TAC) surgery, a pressure-volume overload model of HF. Young euglycemic Dpp4-/- mice exhibited a cardioprotective response following TAC 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 analysis of mechanisms linking fibrosis, inflammation and impaired ventricular function to DPP4 inhibition in preclinical studies.
- Received September 2, 2015.
- Accepted December 7, 2015.
- © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.