title: Dipeptidyl peptidase-4 inhibition attenuates arrhythmias via a protein kinase A-dependent pathway in infarcted hearts.
abstract: 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).
  
  
  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-1expression 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 ofHO-1expression in a cAMP/PKA/CREB-dependent antioxidant pathway in non-diabetic infarcted rats.
authors.affiliation: Department of Medicine, Cardiology Section, China Medical University-An Nan Hospital.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Chen
authors.forename: Nen-Chung
authors.initials: NC
authors.lastname: Chang
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology*; D020932:Nerve Growth Factor / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D000068900:Sitagliptin Phosphate / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D054873:Dipeptidyl-Peptidase IV Inhibitors; D020662:Guanine Nucleotide Exchange Factors; C526973:Rapgef3 protein, rat; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate