AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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 / Vellecco, Valentina; Mitidieri, Emma; Gargiulo, Anna; Brancaleone, V; Matassa, DANILO SWANN; Klein, T; Esposito, Franca; Cirino, Giuseppe; Bucci, Mariarosaria. - In: DIABETES, OBESITY AND METABOLISM. - ISSN 1462-8902. - 18:12(2016), pp. 1236-1243. [10.1111/dom.12750]

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.

VELLECCO, VALENTINA
Co-primo
;
MITIDIERI, EMMA
Co-primo
Investigation
;
GARGIULO, ANNA;MATASSA, DANILO SWANN;ESPOSITO, FRANCA;CIRINO, GIUSEPPE
Penultimo
;
BUCCI, MARIAROSARIA
Ultimo
2016

Abstract

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
2016
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 / Vellecco, Valentina; Mitidieri, Emma; Gargiulo, Anna; Brancaleone, V; Matassa, DANILO SWANN; Klein, T; Esposito, Franca; Cirino, Giuseppe; Bucci, Mariarosaria. - In: DIABETES, OBESITY AND METABOLISM. - ISSN 1462-8902. - 18:12(2016), pp. 1236-1243. [10.1111/dom.12750]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/640785
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