title: A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance.
abstract: To what extent hypoxia alters the adenosine (ADO) system and impacts on cardiac function during embryogenesis is not known. Ectonucleoside triphosphate diphosphohydrolase (CD39), ecto-5'-nucleotidase (CD73), adenosine kinase (AdK), adenosine deaminase (ADA), equilibrative (ENT1,3,4), and concentrative (CNT3) transporters and ADO receptors A1, A2A, A2B, and A3 constitute the adenosinergic system. During the first 4 days of development chick embryos were exposed in ovo to normoxia followed or not followed by 6 h hypoxia. ADO and glycogen content and mRNA expression of the genes were determined in the atria, ventricle, and outflow tract of the normoxic (N) and hypoxic (H) hearts. Electrocardiogram and ventricular shortening of the N and H hearts were recorded ex vivo throughout anoxia/reoxygenation ± ADO. Under basal conditions, CD39, CD73, ADK, ADA, ENT1,3,4, CNT3, and ADO receptors were differentially expressed in the atria, ventricle, and outflow tract. In H hearts ADO level doubled, glycogen decreased, and mRNA expression of all the investigated genes was downregulated by hypoxia, except for A2A and A3 receptors. The most rapid and marked downregulation was found for ADA in atria. H hearts were arrhythmic and more vulnerable to anoxia-reoxygenation than N hearts. Despite downregulation of the genes, exposure of isolated hearts to ADO 1) preserved glycogen through activation of A1 receptor and Akt-GSK3β-GS pathway, 2) prolonged activity and improved conduction under anoxia, and 3) restored QT interval in H hearts. Thus hypoxia-induced downregulation of the adenosinergic system can be regarded as a coping response, limiting the detrimental accumulation of ADO without interfering with ADO signaling.
authors: Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Switzerland; and National Center for Scientific Research, Center for Molecular Biophysics, Orléans, France.
authors: Elodie
authors: E
authors: Robin
authors: Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Switzerland; and.
authors: Fabrice
authors: F
authors: Marcillac
authors: Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Switzerland; and eric.raddatz@unil.ch.
authors: Eric
authors: E
authors: Raddatz
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism; D000222:Adaptation, Physiological; D000241:Adenosine / Q000378:metabolism*; D000248:Adenosine Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001081:Apyrase / Q000235:genetics / Q000378:metabolism; D002642:Chick Embryo; D004734:Energy Metabolism; D033705:Equilibrative Nucleoside Transport Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000196:embryology* / Q000503:physiopathology; D000860:Hypoxia / Q000196:embryology* / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D038081:Organogenesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D033705:Equilibrative Nucleoside Transport Proteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D018047:Receptors, Purinergic P1; C065171:cif nucleoside transporter; D006003:Glycogen; D006006:Glycogen Synthase; D000248:Adenosine Kinase; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine
keywords: adenosine signaling; anoxia-reoxygenation; arrhythmias; glycogen metabolism; hypoxia
references: Anal Biochem. 1972 Oct;49(2):492-7
references: 4404286
references: Biol Neonate. 1991;59(5):294-302
references: 1908323
references: Life Sci. 1988;43(23):1851-9
references: 2849008
references: J Mol Cell Cardiol. 2011 Dec;51(6):945-54
references: 21907719
references: Eur J Pharmacol. 2001 Feb 23;414(1):55-62
references: 11230995
references: Physiology (Bethesda). 2006 Feb;21:29-37
references: 16443820
references: Am J Physiol. 1997 Jul;273(1 Pt 2):H501-5
references: 9249524
references: Am J Physiol Regul Integr Comp Physiol. 2001 Aug;281(2):R401-7
references: 11448841
references: J Morphol. 1951 Jan;88(1):49-92
references: 24539719
references: Animal. 2007 Nov;1(10):1467-71
references: 22444919
references: Am J Physiol Heart Circ Physiol. 2011 Feb;300(2):H507-13
references: 21112945
references: Physiol Rev. 1999 Jul;79(3):635-59
references: 10390514
references: Pediatr Res. 2006 Jan;59(1):116-20
references: 16327005
references: Birth Defects Res A Clin Mol Teratol. 2008 Mar;82(3):121-30
references: 18186126
references: J Physiol. 2007 Dec 15;585(Pt 3):911-7
references: 17962335
references: J Biol Chem. 2012 Aug 3;287(32):26688-701
references: 22692208
references: Mol Cell Biochem. 2010 Jul;340(1-2):239-47
references: 20306288
references: J Thorac Cardiovasc Surg. 2012 Jul;144(1):250-5
references: 22329983
references: Acta Physiol (Oxf). 2015 Feb;213(2):303-20
references: 25363044
references: Dev Dyn. 2006 Jan;235(1):124-31
references: 16110503
references: Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9697-702
references: 17522253
references: Cell Res. 2006 Jun;16(6):548-58
references: 16775626
references: Pharmacol Ther. 2013 Oct;140(1):92-111
references: 23764371
references: J Cardiovasc Electrophysiol. 2006 Dec;17(12):1350-9
references: 17014683
references: J Biol Chem. 2004 Apr 9;279(15):14871-8
references: 14744852
references: Cardiovasc Res. 2005 Mar 1;65(4):803-12
references: 15721860
references: Dev Dyn. 2001 Feb;220(2):175-86
references: 11169851
references: Pediatr Res. 2001 Mar;49(3):363-72
references: 11228262
references: Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2585-9
references: 11709426
references: Am J Physiol Regul Integr Comp Physiol. 2002 Aug;283(2):R379-88
references: 12121851
references: Basic Res Cardiol. 2011 May;106(3):355-69
references: 21279516
references: Curr Mol Med. 2010 Oct;10(7):653-66
references: 20712587
references: Biochem J. 1998 Dec 1;336 ( Pt 2):337-43
references: 9820809
references: BMC Dev Biol. 2010;10:57
references: 20509906
references: Br J Pharmacol. 1999 Sep;128(1):197-205
references: 10498852
references: J Mol Cell Cardiol. 2001 Jan;33(1):121-9
references: 11133228
references: Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H820-35
references: 21193588
references: J Cardiovasc Pharmacol. 2013 Aug;62(2):192-8
references: 23609329
references: Eur J Obstet Gynecol Reprod Biol. 1999 Jun;84(2):155-72
references: 10428339
references: Basic Res Cardiol. 1995 May-Jun;90(3):234-9
references: 7575376
references: Am J Physiol Regul Integr Comp Physiol. 2008 Aug;295(2):R583-95
references: 18509101
references: Circulation. 1996 Aug 15;94(4):734-41
references: 8772696
references: Mol Cell Biochem. 2006 Jul;287(1-2):165-75
references: 16718382
references: Circ Res. 2008 Nov 7;103(10):1139-46
references: 18849322
references: Emerg Med J. 2004 Jul;21(4):408-10
references: 15208219
references: Birth Defects Res C Embryo Today. 2007 Sep;81(3):215-28
references: 17963271
references: Cell. 2008 Jul 25;134(2):279-90
references: 18662543
references: FASEB J. 1995 Mar;9(5):359-65
references: 7896004
references: Ann Cardiol Angeiol (Paris). 2006 Apr;55(2):79-89
references: 16708991
references: Dev Biol. 2004 Mar 15;267(2):294-308
references: 15013795
references: Pediatr Res. 2009 Mar;65(3):279-84
references: 19033883
references: Dev Dyn. 2010 Jul;239(7):1941-9
references: 20549739
references: Annu Rev Physiol. 2012;74:153-75
references: 21942704
references: J Mol Cell Cardiol. 1996 May;28(5):1165-76
references: 8762052
references: Dev Dyn. 2006 Sep;235(9):2592-602
references: 16881058
references: Annu Rev Physiol. 2008;70:51-71
references: 17850210
references: J Mol Cell Cardiol. 2013 Oct;63:14-25
references: 23837961
references: FASEB J. 2006 Jun;20(8):1251-3
references: 16632594
references: Curr Med Chem. 2011;18(8):1164-87
references: 21291368
references: Int J Microcirc Clin Exp. 1991 Nov;10(4):359-71
references: 1778679
references: Handb Exp Pharmacol. 2009;(193):161-88
references: 19639282
references: Arterioscler Thromb Vasc Biol. 2012 Apr;32(4):851-5
references: 22423036