CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury

D Köhler, T Eckle, M Faigle, A Grenz, M Mittelbronn… - Circulation, 2007 - Am Heart Assoc
D Köhler, T Eckle, M Faigle, A Grenz, M Mittelbronn, S Laucher, ML Hart, SC Robson
Circulation, 2007Am Heart Assoc
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 …
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 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.
Am Heart Assoc