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

1
Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, Szeged University, H-6726 Szeged, Hungary
2
Laboratory Animal Research Center, College of Arts and Sciences, Qatar University, Doha 2713, Qatar
3
Department of Physiology, Anatomy and Neuroscience, Interdisciplinary Excellence Center, Szeged University, H-6726 Szeged, Hungary
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(10), 3226; https://doi.org/10.3390/ijms19103226
Received: 3 July 2018 / Revised: 12 October 2018 / Accepted: 15 October 2018 / Published: 18 October 2018
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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. View Full-Text
Keywords: ischemia-reperfusion injury; infarct size; dipeptidyl-peptidase-4; DPP-4 inhibitors; NOS activity; transient receptor potential channels; Calcitonin gene related peptide; endothelial nitric oxide synthase ischemia-reperfusion injury; infarct size; dipeptidyl-peptidase-4; DPP-4 inhibitors; NOS activity; transient receptor potential channels; Calcitonin gene related peptide; endothelial nitric oxide synthase
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Al-awar, A.; Almási, N.; Szabó, R.; Takacs, I.; Murlasits, Z.; Szűcs, G.; Török, S.; Pósa, A.; Varga, C.; Kupai, K. Novel Potentials of the DPP-4 Inhibitor Sitagliptin against Ischemia-Reperfusion (I/R) Injury in Rat Ex-Vivo Heart Model. Int. J. Mol. Sci. 2018, 19, 3226.

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