title: Sitagliptin reduces inflammation, fibrosis and preserves diastolic function in a rat model of heart failure with preserved ejection fraction.
abstract: OBJECTIVE
  Heart failure with preserved ejection fraction (HFpEF) is a systemic syndrome driven by co-morbidities, and its pathophysiology is poorly understood. Several studies suggesting that dipeptidyl peptidase 4 (DPP4) might be involved in the pathophysiology of heart failure have prompted experimental and clinical investigations of DPP4 inhibitors in the cardiovascular system. Here we have investigated whether the DPP4 inhibitor sitagliptin affected the progression of HFpEF independently of its effects on glycaemia.
  
  
  METHODS
  Seven-week-old Dahl salt-sensitive rats were fed a high-salt diet for 5 weeks to induce hypertension. Then the rats continued with the high-salt diet and were treated with either sitagliptin (10 mg·kg-1) or vehicle for the following 8 weeks. Blood pressure and cardiac function were measured in vivo. Histochemical and molecular biology analyses of myocardium were used to assay cytokines, fibrotic markers, DPP4 and glucagon-like peptide-1 (GLP-1)/GLP-1 receptor.
  
  
  RESULTS
  Treatment with sitagliptin attenuated diastolic dysfunction, reduced mortality and reduced cardiac DPP4 activity, along with increased circulating GLP-1 and myocardial expression of GLP-1 receptors. Myocardial levels of pro-inflammatory cytokines (TNF-α, IL-6 and CCL2) were reduced. Sitagliptin treatment decreased the levels of endothelial NOS monomer, responsible for generation of ROS, while the amount of NO-producing dimeric form increased. Markers of oxidative and nitrosative stress were decreased. Moreover, increased collagen deposition and activation of pro-fibrotic signalling, inducing elevated myocardial stiffness, were attenuated by sitagliptin treatment.
  
  
  CONCLUSIONS
  Sitagliptin positively modulated active relaxation and passive diastolic compliance by decreasing inflammation-related endothelial dysfunction and fibrosis, associated with HFpEF.
  
  
  BACKGROUND
  This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Cappetta
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Russo
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Rivellino
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.
authors.forename: Loreta Pia
authors.initials: LP
authors.lastname: Ciuffreda
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors.forename: Fiorentina
authors.initials: F
authors.lastname: Roviezzo
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Piegari
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.
authors.forename: Liberato
authors.initials: L
authors.lastname: Berrino
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Angelis
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005355:Fibrosis; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D020303:Rats, Inbred Dahl; D000068900:Sitagliptin Phosphate / Q000494:pharmacology / Q000627:therapeutic use*; D013318:Stroke Volume
chemical_list: D000893:Anti-Inflammatory Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D009569:Nitric Oxide; D052216:Glucagon-Like Peptide 1; C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate