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.
Diabetes Obes Metab
; 18(12): 1236-1243, 2016 12.
Article
em En
| MEDLINE
| ID: mdl-27460695
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Aorta
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Vasodilatação
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Óxido Nítrico Sintase Tipo III
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Caveolina 1
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Inibidores da Dipeptidil Peptidase IV
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Linagliptina
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article