title: Saxagliptin prevents vascular remodeling and oxidative stress in db/db mice. Role of endothelial nitric oxide synthase uncoupling and cyclooxygenase.
abstract: To explore the hypothesis that DPP-IV are involved in the diabetes-induced vascular damage, we assessed the vascular effects of chronic administration of saxagliptin (Saxa) or metformin (Met) in db/db mice, a model of type 2 diabetes, evaluating vascular structure and endothelial function in mesenteric small arteries. The increases in media/lumen and media cross sectional area were prevented by Saxa. In db/db, the blunted response to acetylcholine was only marginally affected by L-NAME (NO-synthase inhibitor), improved by SC-560 (cyclooxygenase-1 inhibitor) or SQ-29548 (thromboxane receptor antagonist), and totally restored by Apocynin (NAD(P)H-oxidase inhibitor). DFU (cyclooxygenase-2 inhibitor) had no effect. Saxa improved acetylcholine-induced relaxation, which returned partially sensitive to the inhibition of L-NAME. Dihydroethidium staining revealed an increased intravascular superoxide production in db/db, attenuated by L-NAME and Saxa, and abrogated by apocynin. The dimer/monomer ratio of endothelial NOS was decreased in db/db mice and restored by Saxa. Cyclooxygenase-1 and thromboxane-A2 receptor expression, higher in db/db, was down-regulated by Saxa. Met treatment did not modify any of the abnormal vascular responses. Saxa reverses vascular hypertrophic remodeling and ameliorates NO availability in small arteries from db/db mice through the abrogation of NAD(P)H oxidase-driven eNOS uncoupling and by reducing the action of cyclooxygenase-1-derived vasoconstrictors downregulating the expression of thromboxane-prostanoid receptors.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. Electronic address: anna.solini@med.unipi.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Solini
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Duranti
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Taddei
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Natali
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Virdis
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D066253:Vascular Remodeling / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D052246:Cyclooxygenase 2 Inhibitors; D004151:Dipeptides; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011720:Pyrazoles; C115461:SC 560; D009569:Nitric Oxide; C045749:SQ 29548; C502994:saxagliptin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D000218:Adamantane; D019331:NG-Nitroarginine Methyl Ester
keywords: COX; DPP-IV inhibitors; Endothelium; KR-62436 (PubChem CID: 11403745); Microcirculation; Oxidative stress; Saxagliptin (PubChem CID: 66576989); Sodium nitroprusside anhydrous (PubChem CID: 11963579); l-nitroarginine methylester (PubChem CID: 39836)