CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury.
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.
Köhler
David
D
Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany.
Eckle
Tobias
T
Faigle
Marion
M
Grenz
Almut
A
Mittelbronn
Michel
M
Laucher
Stefanie
S
Hart
Melanie L
ML
Robson
Simon C
SC
Müller
Christa E
CE
Eltzschig
Holger K
HK
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*
D015703:Antigens, CD; D000249:Adenosine Monophosphate; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine