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

Salheen SM, Panchapakesan U, Pollock CA, Woodman OL - PLoS ONE (2015)

Bottom Line: Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels.Linagliptin improved endothelial function indicated by a significant increase in responses to ACh.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.

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.

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 (1 μM TRAM-34, 1 μM 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.

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Western blot analysis of protein expression of eNOS (a, 130 kDa), eNOS dimers and monomers (b, 260 kDa) and Nox2 Nox2 (c, 58 kDa) in the normal and diabetic mesenteric arteries with or without linagliptin treatment.In diabetic mesenteric arteries, the expression of eNOS significantly reduced and the proportion of eNOS expressed as the dimer reduced, and the expression of Nox2 increased. Treatment with linagliptin increased the expression of eNOS significantly and reduced Nox2 expression and increased the proportion of eNOS expressed as the dimer. Representative blots are shown on each of the corresponding graphs. n = 6 experiments. Results are shown as mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
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pone.0143941.g005: Western blot analysis of protein expression of eNOS (a, 130 kDa), eNOS dimers and monomers (b, 260 kDa) and Nox2 Nox2 (c, 58 kDa) in the normal and diabetic mesenteric arteries with or without linagliptin treatment.In diabetic mesenteric arteries, the expression of eNOS significantly reduced and the proportion of eNOS expressed as the dimer reduced, and the expression of Nox2 increased. Treatment with linagliptin increased the expression of eNOS significantly and reduced Nox2 expression and increased the proportion of eNOS expressed as the dimer. Representative blots are shown on each of the corresponding graphs. n = 6 experiments. Results are shown as mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

Mentions: In diabetic rats, the expression of total eNOS in the mesenteric arteries was significantly reduced as was the proportion of eNOS expressed as the dimer and the expression of Nox2 was significantly increased (Fig 5A, 5B and 5C). Treatment with linagliptin did not affect the expression or dimerization of eNOS nor the expression of Nox2 in normal rats. By contrast, in diabetic mesenteric arteries, after linagliptin treatment there was a significant increase in eNOS, both in total and as a dimer, and a decrease in Nox2 expression (Fig 5A, 5B and 5C).


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

Salheen SM, Panchapakesan U, Pollock CA, Woodman OL - PLoS ONE (2015)

Western blot analysis of protein expression of eNOS (a, 130 kDa), eNOS dimers and monomers (b, 260 kDa) and Nox2 Nox2 (c, 58 kDa) in the normal and diabetic mesenteric arteries with or without linagliptin treatment.In diabetic mesenteric arteries, the expression of eNOS significantly reduced and the proportion of eNOS expressed as the dimer reduced, and the expression of Nox2 increased. Treatment with linagliptin increased the expression of eNOS significantly and reduced Nox2 expression and increased the proportion of eNOS expressed as the dimer. Representative blots are shown on each of the corresponding graphs. n = 6 experiments. Results are shown as mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664283&req=5

pone.0143941.g005: Western blot analysis of protein expression of eNOS (a, 130 kDa), eNOS dimers and monomers (b, 260 kDa) and Nox2 Nox2 (c, 58 kDa) in the normal and diabetic mesenteric arteries with or without linagliptin treatment.In diabetic mesenteric arteries, the expression of eNOS significantly reduced and the proportion of eNOS expressed as the dimer reduced, and the expression of Nox2 increased. Treatment with linagliptin increased the expression of eNOS significantly and reduced Nox2 expression and increased the proportion of eNOS expressed as the dimer. Representative blots are shown on each of the corresponding graphs. n = 6 experiments. Results are shown as mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
Mentions: In diabetic rats, the expression of total eNOS in the mesenteric arteries was significantly reduced as was the proportion of eNOS expressed as the dimer and the expression of Nox2 was significantly increased (Fig 5A, 5B and 5C). Treatment with linagliptin did not affect the expression or dimerization of eNOS nor the expression of Nox2 in normal rats. By contrast, in diabetic mesenteric arteries, after linagliptin treatment there was a significant increase in eNOS, both in total and as a dimer, and a decrease in Nox2 expression (Fig 5A, 5B and 5C).

Bottom Line: Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels.Linagliptin improved endothelial function indicated by a significant increase in responses to ACh.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.

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.

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 (1 μM TRAM-34, 1 μM 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.

Show MeSH
Related in: MedlinePlus