title: The dipeptidyl peptidase-4 inhibitor-sitagliptin modulates calcium dysregulation, inflammation, and PPARs in hypertensive cardiomyocytes.
abstract: BACKGROUND
  Hypertension induces cardiac dysfunction, calcium (Ca(2+)) 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)-α, -γ, and -δ and Ca(2+) homeostasis.
  
  
  OBJECTIVE
  The purpose of this study was to investigate whether DPP-4 inhibitor, sitagliptin, can modulate PPARs and Ca(2+) handling proteins in hypertensive hearts.
  
  
  METHODS
  A Western blot analysis was used to evaluate protein expressions of myocardial PPAR isoforms, tumor necrosis factor (TNF)-α, interleukin (IL)-6, sarcoplasmic reticulum ATPase (SERCA2a), Na(+)-Ca(2+) exchanger (NCX), ryanodine receptor (RyR), voltage-dependent Ca(2+) (CaV1.2), slow-voltage potassium currents (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 (10mg/kg for 4weeks). 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-α and PPAR-δ protein expressions, but had greater cardiac PPAR-γ levels, and TNF-α, IL-6, RAGE, and AT1R 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 Ca(2+) regulation, which may have been caused by its effects on cardiac PPARs, proinflammatory cytokines, and AT1R.
authors.affiliation: Department of General Medicine, College of Medicine, Taipei Medical University, Taiwan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taiwan.
authors.forename: T-I
authors.initials: TI
authors.lastname: Lee
authors.forename: Y-H
authors.initials: YH
authors.lastname: Kao
authors.forename: Y-C
authors.initials: YC
authors.lastname: Chen
authors.forename: J-H
authors.initials: JH
authors.lastname: Huang
authors.forename: M-I
authors.initials: MI
authors.lastname: Hsu
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000067759:Receptor for Advanced Glycation End Products; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015850:Interleukin-6; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D011719:Pyrazines; D000067759:Receptor for Advanced Glycation End Products; D044140:Receptor, Angiotensin, Type 1; D011971:Receptors, Immunologic; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium; D000068900:Sitagliptin Phosphate
keywords: Calcium handling; Cardiomyocytes; DPP-4 inhibitor; Hypertension; Sitagliptin