Novel Potentials of the DPP-4 Inhibitor Sitagliptin against Ischemia-Reperfusion (I/R) Injury in Rat Ex-Vivo Heart Model

Abstract

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral anti-diabetic drugs, implicated in pleiotropic secondary cardioprotective effects. The aim of the study was to unveil the unknown and possible cardioprotective targets that can be exerted by sitagliptin (Sitg) against ischemia-reperfusion (I/R) injury. Male wistar rats received 2 weeks’ Sitg oral treatment of different doses (25, 50, 100, and 150 mg/kg/day), or saline as a Control. Hearts were then isolated and subjected to two different I/R injury protocols: 10 min perfusion, 45 min regional ischemia, and 120 min reperfusion for infarct size (IS) measurement, or: 10 min perfusion, 45 min regional ischemia and 10 min reperfusion for biochemical analysis: nitric oxide synthases (NOSs) and DPP-4 activity, glucagon-like peptide-1 (GLP-1), Calcium, transient receptor potential vanilloid (TRPV)-1 and calcitonin gene-related peptide (CGRP) levels, transient receptor potential canonical (TRPC)-1 and e-NOS protein expression. NOS inhibitor (l-NAME) and TRPV-1 inhibitor (Capsazepine) were utilized to confirm the implication of both signaling mechanisms in DPP-4 inhibition-induced at the level of IS. Findings show that Sitg (50 mg) resulted in significant decrease in IS and DPP-4 activity, and significant increase in GLP-1, NOS activity, e-NOS expression, TRPV-1 level and TRPC-1 expression, compared to controls. Results of CGRP are in line with TRPV-1, as a downstream regulatory effect. NOS system and transient receptor potential (TRP) channels can contribute to DPP-4 inhibition-mediated cardioprotection against I/R injury using Sitagliptin.

Activation of Nrf2 signaling by sitagliptin and quercetin combination against β‐amyloid induced Alzheimer's disease in rats

“…DPP-4 inhibitors increase the glucagon-like peptide 1 hormone (GLP-1) secretion, which successively stimulates the secretion of insulin and suppresses glucagon secretion. Emerging proof has proposed the neuroprotective effects of Sita (Al-Awar et al, 2018;Gupta, Singh, David, & Verma, 2013;Samuel et al, 2019). Number of reported literatures have demonstrated that Sita can increases the GLP-1 level in the brain along with improve the cognitive behaviors in rat model of AD (Civantos et al, 2017).…”

Effect of DPP-4 inhibitor sitagliptin against ischemia-reperfusion (I/R) injury in hyperlipidemic animals

“…Moreover, no significant change was observed in serum Chol and TG levels in animal groups treated with Sitg (50 mg), compared to the controls. According to previous clinical studies, treatment with 50 mg dose of sitagliptin was effective in lowering lipid profile and glucose levels, and reducing DPP-4 activity by approximately 80% in patients with type 2 diabetes (Herman et al 2005;Shigematsu et al 2014) In the contrary of obtained findings from normolipidemic animals (Al-Awar et al 2018), the expected decrease in DPP-4 activity and increase in GLP-1 was not observed in high-fat diet condition. However, treatment with sitagliptin exhibited a significant decrease in DPP-4 protein level measured from heart tissues and aortas.…”

“…We hypothesized that hypercholesterolemia can be associated with increased infarct size, and sitagliptin can decrease its detrimental effect on the heart, clarifying mechanisms underlying this protection. Treatment with Sitg (50 mg) showed a significant decrease in infarct size and increase in cNOS activity in comparison with the control group, while this infarct size-limiting effect was abolished after NOS-inhibition by L-NAME, similarly as in normolipidemic animals (Al-Awar et al 2018). L-NAME is a non-selective NOS inhibitor that inhibits the 3 NOS isoforms: endothelial NOS (e-NOS), inducible NOS (i-NOS) and neuronal NOS (n-NOS).…”

“…DPP-4 inhibitors were extensively studied in healthy animal models as a remedy for cardiovascular disorders; however, the interventional mechanisms of the latter drugs were poorly addressed in diseased models, such as hyperlipidemia. This study was carried out with the aim of extending the results of previous work in normolipidemic animals (Al-Awar et al 2018). In this HF rat model, the effect of hyperlipidemia on the development of myocardial infarction (MI) following a temporary coronary occlusion (ischemia-reperfusion injury) was studied.…”

“…Whether sitagliptin-induced cardioprotection against I/R injury can be mediated by NOS and/or TRP channels in hyperlipidemia is still unknown. Therefore, in this study we aimed to elucidate the possible protective mechanisms of sitagliptin against I/R injury and myocardial infarct size (IS) in a hyperlipidemic rat model, in comparison with the results from normolipidemic animals in our previous study (Al-Awar et al 2018).…”