Abstract
We investigated whether sitagliptin attenuates arrhythmias through inhibiting nerve growth factor (NGF) expression in postinfarcted normoglycemic rats, focusing on cAMP downstream molecules such as PKA and Epac. Male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4 weeks. Post‐infarction was associated with increased oxidative stress and myocardial norepinephrine levels. Compared with vehicle, sitagliptin‐treated rats significantly increased cAMP levels and attenuated oxidative stress and NGF levels. Immunofluorescent studies confirmed that sympathetic hyperinnervation was blunted after sitagliptin. Arrhythmic scores in the sitagliptin‐treated rats were significantly lower than vehicle. Ex vivo studies showed that sitagliptin increased phosphorylated cAMP response element binding protein (CREB), which can be reversed by H‐89 (selective PKA inhibitor), not brefeldin A (selective Epac inhibitor). Heme oxygenase‐1 (HO‐1) expression was significantly increased by a PKA agonist but not by an Epac agonist. HO‐1 expression was attenuated in KG‐501 (a CREB inhibitor)‐treated rats in the presence of a PKA agonist. In conclusions, sitagliptin protects arrhythmias by attenuating NGF‐induced sympathetic innervation via upregulation of HO‐1 expression in a cAMP/PKA/CREB‐dependent antioxidant pathway in the non‐diabetic infarcted rats.
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