Background: The effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on arrhythmias remains unknown. The aim of this study was to investigate whether sitagliptin attenuates arrhythmias through inhibiting nerve growth factor (NGF) expression, focusing on cyclic adenosine monophosphate (cAMP) downstream signaling such as protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). Methods and Results: Male Wistar rats were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after ligating the coronary artery. Post-infarction was associated with increased oxidative stress. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham. Compared with the vehicle, infarcted rats treated with sitagliptin had significantly increased cAMP levels, decreased DPP-4 activity, oxidative stress, NGF levels and immunofluorescence-stained sympathetic hyperinnervation. Arrhythmic scores were significantly lower in the sitagliptin-treated infarcted rats than in vehicle. Ex vivo studies showed that sitagliptin increased the phosphorylated cAMP response element-binding protein (CREB), which can be reversed by H-89 (a PKA inhibitor), not brefeldin A (an Epac inhibitor). Heme oxygenase-1 (HO-1) expression was increased by a PKA agonist but not by an Epac agonist. HO-1 expression was attenuated in KG-501 (a CREB inhibitor)-treated infarcted rats in the presence of a PKA agonist. Conclusions: Sitagliptin protects ventricular arrhythmias by attenuating NGF-induced sympathetic innervation via upregulation of HO-1 expression in a cAMP/PKA/CREB-dependent antioxidant pathway in non-diabetic infarcted rats.
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