Published Online
on October 10, 2007

A more recent version of this article appeared on October 16, 2007

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Submitted on January 12, 2007
Accepted on August 17, 2007

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

David Köhler PhD, Tobias Eckle MD, Marion Faigle BS, Almut Grenz MD, Michel Mittelbronn MD, Stefanie Laucher BS, Melanie L. Hart PhD, Simon C. Robson MD, Christa E. Müller PhD, and Holger K. Eltzschig MD, PhD^*

From the Department of Anesthesiology and Intensive Care Medicine (D.K., T.E., M.F., S.L., H.K.E.), Department of Pharmacology and Toxicology (A.G.), and Institute of Brain Research (M.M.), University Hospital, Tübingen, Germany; Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital (M.L.H.), and Liver and Transplant Centers (S.C.R.), Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; Pharmaceutical Institute, Pharmaceutical Sciences Bonn, University of Bonn, Bonn, Germany (C.E.M.); and Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Health Science Center, Denver (H.K.E.).

^* To whom correspondence should be addressed. E-mail: holger.eltzschig{at}uchsc.edu.

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.

Key words: adenosine • endothelium • enzymes • myocardial infarction • reperfusion

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