CD39/Ectonucleoside Triphosphate Diphosphohydrolase 1 Provides Myocardial Protection During Cardiac Ischemia/Reperfusion Injury

D. Kohler, T. Eckle, M. Faigle, A. Grenz, M. Mittelbronn, S. Laucher, M. L. Hart, S. C. Robson, C. E. Muller, H. K. Eltzschig
2007 Circulation  
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. Methods and Results-As a first step, we used a murine model of myocardial ischemia and in situ preconditioning and
more » ... formed pharmacological studies with polyoxometalate 1, a potent E-NTPDase inhibitor (Na 6 [H 2 W 12 O 40 ]). 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 Ϫ/Ϫ mice exhibited larger infarct sizes with ischemia (cd39 ϩ/ϩ 43.0Ϯ3.3% versus cd39 Ϫ/Ϫ 52%Ϯ1.8; PϽ0.05), and cardioprotection was abrogated by preconditioning (cd39 ϩ/ϩ 13.3%Ϯ1.5 versus cd39 Ϫ/Ϫ 50.5%Ϯ2.8; PϽ0.01). Heightened levels of injury after myocardial ischemia and negligible preconditioning benefits in cd39 Ϫ/Ϫ mice were corrected by infusion of the metabolic product (AMP) or apyrase. Moreover, apyrase treatment of wild-type mice resulted in 43Ϯ4.2% infarct size reduction (PϽ0.01). Conclusions-Taken together, these studies reveal E-NTPDase 1 in cardioprotection and suggest apyrase in the treatment of myocardial ischemia.
doi:10.1161/circulationaha.107.690180 pmid:17909107 fatcat:whltrl2isnb5raawocorsydgae