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. Issue 12 (30th August 2016)

• Record Type: Journal Article
• Authors: Vellecco, Valentina; Mitidieri, Emma; Gargiulo, Antonella; Brancaleone, Vincenzo; Matassa, Danilo; Klein, Thomas; Esposito, Franca; Cirino, Giuseppe; Bucci, Mariarosaria
• Is Part Of: Diabetes, obesity & metabolism. Volume 18:Issue 12(2016)
• Page Start: 1236
• Page End: 1243
• Publication Date: 2016-08-30
• Subjects: caveolin‐1 -- DPP‐4 inhibitors -- GLP‐1 receptor -- NOD mice -- soluble guanylyl cyclase; Diabetes -- Periodicals; Obesity -- Periodicals; Metabolism -- Disorders -- Periodicals; Clinical pharmacology -- Periodicals; 616.462
• DOI: 10.1111/dom.12750
• Languages: English
• ISSNs: 1462-8902

Abstract

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.