title: CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury.
abstract: BACKGROUND
  Extracellular adenosine, generated from extracellular nucleotides via ectonucleotidases, binds to specific receptors and provides cardioprotection from ischemia and reperfusion. In the present study, we studied ecto-enzymatic ATP/ADP-phosphohydrolysis by select members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family during myocardial ischemia.
  
  
  RESULTS
  As a first step, we used a murine model of myocardial ischemia and in situ preconditioning and performed pharmacological studies with polyoxometalate 1, a potent E-NTPDase inhibitor (Na6[H2W12O40]). Polyoxometalate 1 treatment increased infarct sizes and abolished beneficial effects of preconditioning. To define relative contributions of distinct E-NTPDases, we investigated transcriptional responses of E-NTPDases 1 to 3 and 8 to preconditioning. We noted robust and selective induction of E-NTPDase 1 (CD39) transcript and protein. Histological analysis of preconditioned myocardium localized CD39 induction to endothelia and myocytes. Cd39-/- mice exhibited larger infarct sizes with ischemia (cd39+/+ 43.0+/-3.3% versus cd39-/- 52%+/-1.8; P<0.05), and cardioprotection was abrogated by preconditioning (cd39+/+ 13.3%+/-1.5 versus cd39-/- 50.5%+/-2.8; P<0.01). Heightened levels of injury after myocardial ischemia and negligible preconditioning benefits in cd39-/- mice were corrected by infusion of the metabolic product (AMP) or apyrase. Moreover, apyrase treatment of wild-type mice resulted in 43+/-4.2% infarct size reduction (P<0.01).
  
  
  CONCLUSIONS
  Taken together, these studies reveal E-NTPDase 1 in cardioprotection and suggest apyrase in the treatment of myocardial ischemia.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Köhler
authors.forename: Tobias
authors.initials: T
authors.lastname: Eckle
authors.forename: Marion
authors.initials: M
authors.lastname: Faigle
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Stefanie
authors.initials: S
authors.lastname: Laucher
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Hart
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D001081:Apyrase / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D004790:Enzyme Induction; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology*
chemical_list: D015703:Antigens, CD; D000249:Adenosine Monophosphate; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine