Possible vasculoprotective role of linagliptin against sodium arsenite-induced vascular endothelial dysfunction

Abstract

Vascular endothelial dysfunction (VED) interrupts the integrity and function of endothelial lining through enhanced markers of oxidative stress and decrease endothelial nitric oxide synthase (eNOS) expression. The main aim of the present study has been designed to investigate the possible vasculoprotective role of linagliptin against sodium arsenite-induced VED. Sodium arsenite (1.5 mg/kg, i.p., 2 weeks) abrogated the acetylcholine-induced, endothelium-dependent vasorelaxation by depicting the decrease in serum nitrite/nitrate concentration, reduced glutathione level, and simultaneously enhance the thiobarbituric acid reactive substances (TBARS) level, superoxide level, and tumor necrosis factor-alpha. These elevated markers interrupt the integrity of endothelial lining of thoracic aorta which was assessed histologically. The study elicits dose dependent effect of linagliptin (1.5 mg/kg, i.p. and 3 mg/kg, i.p.) or atorvastatin (30 mg/kg, p.o.) treatment, improved the endothelium-dependent independent relaxation, improve the integrity of endothelium lining which was assessed histologically by enhancing the serum nitrite/nitrate level, reduced glutathione level and simultaneously decreasing the TBARS level, superoxide anion level and tumor necrosis factor-alpha (TNF-α) level. L-NAME (25 mg/kg, i.p.), eNOS inhibitor, abrogated the ameliorative potential of linagliptin. However, the ameliorative potential of linagliptin has been enhanced by l-arginine (200 mg/kg, i.p.) which elicits that ameliorative potential of linagliptin was through eNOS signaling cascade and it may be concluded that linagliptin 3 mg/kg, i.p. has more significantly activated the eNOS and decreased the oxidative markers than linagliptin 1.5 mg/kg, i.p. and prevented sodium arsenite-induced VED.

A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes

“…The improvements in microvascular function seen in the present study are consistent with experimental studies using animal models, which have shown that linagliptin has vasodilatory, anti-oxidant and anti-inflammatory properties, and can reduce atherosclerosis, independent of lowering glucose levels [33–35]. Preliminary clinical trials have also shown that linagliptin has the potential to modify microvascular function.…”

<p>Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride</p>

“…Evidence from studies conducted with linagliptin in conditions where endothelial dysfunction is not caused by hyperglycemia seems to support the potential for linagliptin to have beneficial vascular actions, again independent of glucose homeostasis. For example, linagliptin improved endothelial dysfunction in aortae from rats exposed to sepsis34 when oxidative stress was increased by administration of sodium arsenite 6. Linagliptin was also seen to improve endothelium-dependent relaxation in aortae from apolipoprotein-E-deficient mice, an effect that was accompanied by a decrease in oxidative stress and decreased development of atherosclerotic plaques 35.…”

“…Notably, the effect on the endothelium occurred in the absence of any observable linagliptin-induced reduction in plasma glucose concentration. The apparent effect of linagliptin to improve endothelial function, by a mechanism that is independent of any action on glucose concentration, is supported by observations that linagliptin treatment improves impaired endothelial function in mice with elevated lipid levels or where endothelium-dependent relaxation was impaired by sodium arsenite-induced oxidative stress 6. These findings are consistent with observations in diabetic patients, where DPP-4 inhibitors appear to improve endothelium-dependent relaxation in terms of increased flow-mediated dilatation of the brachial artery although it should be noted that not all studies with DPP-4 inhibitors have confirmed this effect 7–9…”

Neuroprotective Properties of Linagliptin: Focus on Biochemical Mechanisms in Cerebral Ischemia, Vascular Dysfunction and Certain Neurodegenerative Diseases

“…Linagliptin seems to promote the normalization of these pathological phenomena. Numerous independent studies proved linagliptin’s influence on NO production and subsequent oxidative stress limitation [17,51,52]. Salheen et al (2015)dowiedli, że linagliptyna działa protekcyjnie na śródbłonek tętnic krezkowych u szczurów z cukrzycą typu 1 niezależnie od GLP-1/GLP-1R.…”