The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Preserves Endothelial Function in Mesenteric Arteries from Type 1 Diabetic Rats without Decreasing Plasma Glucose

Salheen M Salheen,Owen L Woodman,Carol A Pollock,Usha Panchapakesan,William Durante

doi:10.1371/journal.pone.0143941

Salheen M Salheen, Owen L Woodman + Show 3 more

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https://doi.org/10.1371/journal.pone.0143941

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Abstract

The aim of the study was to investigate the effect of the DPP-4 inhibitor linagliptin on the mechanism(s) of endothelium-dependent relaxation in mesenteric arteries from STZ-induced diabetic rats. Both normal and diabetic animals received linagliptin (2 mg/kg) daily by oral gavage for a period of 4 weeks. To measure superoxide generation in mesenteric arteries, lucigenin-enhanced chemiluminescence was used. ACh-induced relaxation of mesenteric arteries was assessed using organ bath techniques and Western blotting was used to investigate protein expression. Pharmacological tools (1μM TRAM-34, 1μM apamin, 100 nM Ibtx, 100 μM L-NNA, 10 μM ODQ) were used to distinguish between NO and EDH-mediated relaxation. Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels. Diabetes reduced responses to ACh but did not affect endothelium-independent responses to SNP. Linagliptin improved endothelial function indicated by a significant increase in responses to ACh. Diabetes impaired the contribution of both nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) to endothelium-dependent relaxation and linagliptin treatment significantly enhanced the contribution of both relaxing factors. Western blotting demonstrated that diabetes also increased expression of Nox2 and decreased expression and dimerization of endothelial NO synthase, effects that were reversed by linagliptin. These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity.

Highlights

Endothelial dysfunction is considered a critical factor in the initiation and development of vascular complications induced by diabetes [1, 2]
A similar dose of linagliptin (1 mg/kg po) to that used in this study (2 mg/kg po) has been demonstrated to effectively inhibit Dipeptidyl peptidase-4 (DPP-4) activity and to increase GLP-1 in Zucker diabetic fatty rats [24] but in this type 1 model of diabetes, where the beta pancreatic cells are destroyed by necrosis, it is not possible to elevate insulin secretion to decrease glucose
Treatment of diabetic rats with linagliptin improved the contribution of both nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) to endothelium-dependent relaxation, effects which were associated with an increased expression of total endothelial NO synthase (eNOS), improved eNOS dimerization and reduced vascular Nox2 expression

Summary

Introduction

Endothelial dysfunction is considered a critical factor in the initiation and development of vascular complications induced by diabetes [1, 2]. Previous studies have demonstrated additional beneficial effects of GLP-1 in situations such as in the regulation of endothelial function and cardiac remodeling [14,15,16,17] and the DPP-4 inhibitors have been reported to reduce the impairment of cardiac diastolic function in insulin resistant male Zucker obese rats [18], to improve the obesity-related glomerulopathy in Zucker obese rat [19], to ameliorate dysfunction in rat aortic artery in experimental sepsis [20] and to reduce oxidative stress in vascular endothelial cells [21]. We have recently found that acute treatment with linagliptin ameliorates vascular dysfunction in mesenteric arteries exposed to high concentration of glucose (40 mM) demonstrating a beneficial action independently of any glucose lowering effect [8]

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