title: Vascular effects of linagliptin in non-obese diabetic mice are glucose-independent and involve positive modulation of the endothelial nitric oxide synthase (eNOS)/caveolin-1 (CAV-1) pathway.
abstract: To test the effect of linagliptin in non-obese diabetic (NOD) mice, a murine model of type 1 diabetes, to unveil a possible direct cardiovascular action of dipeptidyl peptidase 4 (DPP-4) inhibitors beyond glycaemia control.
  
  
  
  NOD mice were grouped according to glycosuria levels as NODI: none; NODII: high; NODIII: severe. Linagliptin treatment was initiated once they reached NODII levels. Vascular reactivity was assessed ex vivo on aorta harvested from mice upon reaching NODIII level. In a separate set of experiments, the effect of linagliptin was tested directly in vitro on vessels harvested from untreated NODIII, glucagon-like peptide-1 (GLP-1) receptor knockout and soluble guanylyl cyclase-α1 knockout mice. Molecular and cellular studies were performed on endothelial and endothelial nitric oxide synthase (eNOS)-transfected cells.
  
  
  
  In this ex vivo vascular study, endothelium-dependent vasorelaxation was ameliorated and eNOS/nitric oxide (NO)/soluble guanylyl cyclase (sGC) signalling was enhanced. In the in vitro vascular study, linagliptin exerted a direct vasodilating activity on vessels harvested from both normo- or hyperglycaemic mice. The effect was independent from GLP-1/GLP-1 receptor (GLP-1R) interaction and required eNOS/NO/sGC pathway activation. Molecular studies performed on endothelial cells show that linagliptin rescues eNOS from caveolin-1 (CAV-1)-binding in a calcium-independent manner.
  
  
  
  Linagliptin, by interfering with the protein-protein interaction CAV-1/eNOS, led to an increased eNOS availability, thus enhancing NO production. This mechanism accounts for the vascular effect of linagliptin that is independent from glucose control and GLP-1/GLP-1R interaction.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vellecco
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Mitidieri
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Gargiulo
authors.affiliation: Department of Science, University of Basilicata, Potenza, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Brancaleone
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Matassa
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG Cardio-metabolic Diseases, Ingelheim am Rhein, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D001808:Blood Vessels / Q000187:drug effects; D051242:Caveolin 1 / Q000187:drug effects* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics; D000069476:Linagliptin / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D051242:Caveolin 1; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D009569:Nitric Oxide; D000069476:Linagliptin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000071756:Soluble Guanylyl Cyclase
keywords: DPP-4 inhibitors; GLP-1 receptor; NOD mice; caveolin-1; soluble guanylyl cyclase