The dipeptidyl peptidase-4 inhibitor-sitagliptin modulates calcium dysregulation, inflammation, and PPARs in hypertensive cardiomyocytes

Background: Hypertension induces cardiac dysfunction, calcium (Ca2+) dysregulation, and arrhythmogenesis. Dipeptidyl peptidase (DPP)-4 inhibitors, an antidiabetic agent with anti-inflammation and anti-hypertension potential, may regulate peroxisome proliferator-activated receptors (PPARs)-alpha, -gamma, and -delta and Ca2+ homeostasis. Objective: The purpose of this study was to investigate whether DPP-4 inhibitor, sitagliptin, can modulate PPARs and Ca2+ handling proteins in hypertensive hearts. Methods: AWestern blot analysis was used to evaluate protein expressions of myocardial PPAR isoforms, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, sarcoplasmic reticulum ATPase (SERCA2a), Na+-Ca2+ exchanger (NCX), ryanodine receptor (RyR), voltage-dependent Ca2+ (CaV1.2), slow-voltage potassiumcurrents (Kvs), angiotensin II type 1 receptor (AT1R), and receptor of advanced glycated end-products (RAGE) from Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and SHR treated with sitagliptin (10 mg/kg for 4 weeks). Conventional microelectrodes were used to record action potentials (APs) in the ventricular myocytes from each group. Results: Compared to the control group, SHR had lower cardiac PPAR-a and PPAR-d protein expressions, but had greater cardiac PPAR-alpha levels, and TNF-alpha, IL-6, RAGE, and ATIR protein expressions, which were ameliorated in the sitagliptin-treated SHR. SHR had prolonged QT interval and AP duration with less SERCA2a and RyR, and greater CaV1.2 expressions, which were also attenuated in sitagliptin-treated SHR. Conclusions: Sitagliptin significantly changed the cardiac electrophysiological characteristics and Ca2+ regulation, which may have been caused by its effects on cardiac PPARs, proinflammatory cytokines, and ATIR. (C) 2013 Elsevier Ireland Ltd. All rights reserved.