Dipeptidyl peptidase-4 inhibition attenuates arrhythmias via a protein kinase A-dependent pathway in infarcted hearts.

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). METHODSANDRESULTS 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.

[1]  N. Chang,et al.  Antiarrhythmic effect of lithium in rats after myocardial infarction by activation of Nrf2/HO-1 signaling. , 2014, Free radical biology & medicine.

[2]  M. Mocanu,et al.  Dipeptidyl peptidase-4 inhibitors and GLP-1 reduce myocardial infarct size in a glucose-dependent manner , 2013, Cardiovascular Diabetology.

[3]  Kazutaka Aonuma,et al.  Epidemiology of arrhythmias and sudden cardiac death in Asia. , 2013, Circulation journal : official journal of the Japanese Circulation Society.

[4]  S. Hokimoto,et al.  Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. , 2013, Circulation journal : official journal of the Japanese Circulation Society.

[5]  M. Hansen,et al.  Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons , 2012, Hearing Research.

[6]  G. Lamb,et al.  Differential effects of peroxynitrite on contractile protein properties in fast- and slow-twitch skeletal muscle fibers of rat. , 2011, Journal of applied physiology.

[7]  M. Okada,et al.  Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner , 2010, Diabetes.

[8]  R. D. de Boer,et al.  Glucagon-Like Peptide 1 Prevents Reactive Oxygen Species–Induced Endothelial Cell Senescence Through the Activation of Protein Kinase A , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[9]  F. Lezoualc’h,et al.  Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology , 2010, Pflügers Archiv - European Journal of Physiology.

[10]  R. Henkelman,et al.  Genetic Deletion or Pharmacological Inhibition of Dipeptidyl Peptidase-4 Improves Cardiovascular Outcomes After Myocardial Infarction in Mice , 2010, Diabetes.

[11]  Andrew J. Murray,et al.  cAMP-Dependent Axon Guidance Is Distinctly Regulated by Epac and Protein Kinase A , 2009, The Journal of Neuroscience.

[12]  Constancio González,et al.  EPAC signalling pathways are involved in low PO2 chemoreception in carotid body chemoreceptor cells , 2009, The Journal of physiology.

[13]  P. Leung,et al.  Combination of the Dipeptidyl Peptidase IV Inhibitor LAF237 [(S)-1-[(3-Hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] with the Angiotensin II Type 1 Receptor Antagonist Valsartan [N-(1-Oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]methyl]-l-valine] Enhances Pancreatic Islet Morpholo , 2008, Journal of Pharmacology and Experimental Therapeutics.

[14]  G. Baillie,et al.  EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation , 2008, Proceedings of the National Academy of Sciences.

[15]  K. Kristiansen,et al.  Cyclic AMP (cAMP)-Mediated Stimulation of Adipocyte Differentiation Requires the Synergistic Action of Epac- and cAMP-Dependent Protein Kinase-Dependent Processes , 2008, Molecular and Cellular Biology.

[16]  N. Chang,et al.  Effect of ATP-sensitive potassium channel agonists on ventricular remodeling in healed rat infarcts. , 2008, Journal of the American College of Cardiology.

[17]  YoshihikoSaito,et al.  Enhanced Functional Gap Junction Neoformation by Protein Kinase A–Dependent and Epac-Dependent Signals Downstream of cAMP in Cardiac Myocytes , 2005 .

[18]  K. Gardner,et al.  Identification of small-molecule antagonists that inhibit an activator: coactivator interaction. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  L. Barbeito,et al.  Stimulation of nerve growth factor expression in astrocytes by peroxynitrite. , 2004, In vivo.

[20]  H. Okano,et al.  Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression. , 2004, The Journal of clinical investigation.

[21]  J. Cook,et al.  Transcriptional regulation of the heme oxygenase-1 gene via the stress response element pathway. , 2003, Current pharmaceutical design.

[22]  D. Ginty,et al.  Function and Regulation of CREB Family Transcription Factors in the Nervous System , 2002, Neuron.

[23]  Marc Montminy,et al.  Transcriptional regulation by the phosphorylation-dependent factor CREB , 2001, Nature Reviews Molecular Cell Biology.

[24]  H. Schipper,et al.  Role of heme oxygenase‐1 in the regulation of manganese superoxide dismutase gene expression in oxidatively‐challenged astroglia , 2000, Journal of cellular physiology.

[25]  T A Denton,et al.  Relationship between regional cardiac hyperinnervation and ventricular arrhythmia. , 2000, Circulation.

[26]  M. Fishbein,et al.  Nerve sprouting and sudden cardiac death. , 2000, Circulation research.

[27]  A. Wittinghofer,et al.  Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP , 1998, Nature.

[28]  A. Colangelo,et al.  β-Adrenergic receptor-induced activation of nerve growth factor gene transcription in rat cerebral cortex involves CCAAT/enhancer-binding protein δ , 1998 .

[29]  T. Kietzmann,et al.  The rat heme oxygenase-1 gene is transcriptionally induced via the protein kinase A signaling pathway in rat hepatocyte cultures. , 1998, Molecular pharmacology.

[30]  S. Tonegawa,et al.  Reduced stress defense in heme oxygenase 1-deficient cells. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  W. Snider,et al.  Functions of the neurotrophins during nervous system development: What the knockouts are teaching us , 1994, Cell.

[32]  S. Taylor,et al.  Identifying the molecular switches that determine whether (Rp)-cAMPS functions as an antagonist or an agonist in the activation of cAMP-dependent protein kinase I. , 1991, Biochemistry.

[33]  R. Vracko,et al.  Fate of nerve fibers in necrotic, healing, and healed rat myocardium. , 1990, Laboratory investigation; a journal of technical methods and pathology.

[34]  T. Curran,et al.  Redox regulation of fos and jun DNA-binding activity in vitro. , 1990, Science.

[35]  N. Chang,et al.  Effect of N-acetylcysteine on sympathetic hyperinnervation in post-infarcted rat hearts. , 2010, Cardiovascular research.

[36]  M. Stegall,et al.  Forskolin suppresses insulin gene transcription in islet beta-cells through a protein kinase A-independent pathway. , 2003, Cellular signalling.

[37]  A. Colangelo,et al.  beta-adrenergic receptor-induced activation of nerve growth factor gene transcription in rat cerebral cortex involves CCAAT/enhancer-binding protein delta. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. K. Gulati,et al.  Evaluation of acellular and cellular nerve grafts in repair of rat peripheral nerve. , 1988, Journal of neurosurgery.