title: Inhibition of Dipeptidyl Peptidase-4 Impairs Ventricular Function and Promotes Cardiac Fibrosis in High Fat-Fed Diabetic Mice.
abstract: 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.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Mulvihill
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Elodie M
authors.initials: EM
authors.lastname: Varin
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Ussher
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: K W Annie
authors.initials: KW
authors.lastname: Bang
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Tahmid
authors.initials: T
authors.lastname: Abdullah
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Baggio
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada drucker@lunenfeld.ca.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D006332:Cardiomegaly; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005355:Fibrosis / Q000235:genetics; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D007249:Inflammation; D000069450:Liraglutide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D059467:Transcriptome; D014230:Triazoles / Q000494:pharmacology; D016276:Ventricular Function / Q000187:drug effects* / Q000235:genetics; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000235:genetics
chemical_list: D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; C570834:MK0626; D012333:RNA, Messenger; D014230:Triazoles; D000069450:Liraglutide; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse