title: Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats.
abstract: Myocardial infarction (MI) was associated with insulin resistance, in which resistin acts as a critical mediator. We aimed to determine whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, can attenuate arrhythmias by regulating resistin-dependent nerve growth factor (NGF) expression in postinfarcted rats. Normoglycaemic male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after operation. Post-infarction was associated with increased myocardial noradrenaline [norepinephrine (NE)] levels and sympathetic hyperinnervation. Compared with vehicle, sympathetic innervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Furthermore, sitagliptin was associated with reduced resistin expression and increased Akt activity. Ex vivo studies showed that glucose-dependent insulinotropic polypeptide (GIP) infusion, but not glucagon-like peptide-1 (GLP-1), produced similar reduction in resistin levels to sitagliptin in postinfarcted rats. Furthermore, the attenuated effects of sitagliptin on NGF levels can be reversed by wortmannin (a phosphatidylinositol 3-kinase antagonist) and exogenous resistin infusion. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation in the non-diabetic infarcted rats. Sitagliptin attenuated resistin expression via the GIP-dependent pathway, which inhibited sympathetic innervation through a signalling pathway involving phosphatidylinositol 3-kinase (PI3K) and Akt protein.
authors.affiliation: Department of Medicine, Cardiology Section, China Medical University-An Nan Hospital, Tainan 70911, Taiwan Department of Medicine, China Medical University, Taichung 40447, Taiwan Cardiovascular Research Laboratory, China Medical University Hospital, Taichung 40447, Taiwan Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
authors.affiliation: Department of Medicine, Cardiology Section, China Medical University-An Nan Hospital, Tainan 70911, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan ncchang@tmu.edu.tw.
authors.forename: Nen-Chung
authors.initials: NC
authors.lastname: Chang
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000493:pharmacokinetics*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D052243:Resistin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000068900:Sitagliptin Phosphate / Q000494:pharmacology*
chemical_list: D052243:Resistin; C499622:Retn protein, rat; D005749:Gastric Inhibitory Polypeptide; C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate
keywords: glucose-dependent insulinotropic polypeptide; myocardial infarction; nerve growth factor; resistin; sympathetic nerve
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