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.
Highlights
Cardiovascular disorders, mainly ischemic heart disease, are the major cause of morbidity and mortality in patients with diabetes mellitus [1]
After two weeks of daily oral administration of four different doses of the same dipeptidyl peptidase-4 (DPP-4) inhibitor (Sitagliptin (Sitg)), prior to ischemia-reperfusion injury and after subjecting the heart tissues to 45 min of regional ischemia and 120 min of reperfusion, the Sitg (50 mg/kg/day) treated group exhibited a significant decrease in infarct size (22.20 ± 2.03%) compared to the Control group (44.89 ± 4.02%)
Measurements of glucagon-like peptide-1 (GLP-1) level from heart tissues subjected to brief reperfusion (10 min), revealed a significant increase (44.98 ± 4.02 ng/mL) in the Sitg (50 mg) treated group compared to the Controls (22.20 ± 2.03 ng/mL)
Summary
Cardiovascular disorders, mainly ischemic heart disease, are the major cause of morbidity and mortality in patients with diabetes mellitus [1]. Reestablishing blood flow is considered to be the best therapeutic strategy and conventional remedy in myocardial infarction to prevent the myocardium from further damage, but apoptosis of cardiomyocytes is inevitable in ischemia/reperfusion (I/R) injury [2]. Oral dipeptidyl peptidase-4 (DPP-4) inhibitors have recently been introduced as anti-hyperglycemic drugs [4] that can exert either beneficial [5] or harmful [6] pleiotropic effects on the cardiovascular system. DPP-IV inhibitors prevent the degradation of the incretin hormones, namely glucagon-like peptide-1 (GLP-1) [7] that regulates glucose homeostasis after food ingestion [8]. Activation of GLP-1 by DPP-4 inhibitors and GLP-1 analogs, limits myocardial infarct size (IS) and causes upregulation in intracellular cascades like protein kinases, Akt/P-Akt, and extracellular signal-regulated kinases (ERK1/2) with protective profile against ischemia-reperfusion injury [4]. Mechanisms of protection are still unclear, and a protective drug against infarct size is still unknown
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