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

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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

188 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)1784-1794
Number of pages11
JournalCirculation
Volume116
Issue number16
DOIs
Publication statusPublished - Oct 2007
Externally publishedYes

Keywords

  • Adenosine
  • Endothelium
  • Enzymes
  • Myocardial infarction
  • Reperfusion

Fingerprint

Dive into the research topics of 'CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury'. Together they form a unique fingerprint.

Cite this