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

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.

• Authors: David Köhler, Tobias Eckle, Marion Faigle, Almut Grenz, Michel Mittelbronn, Stefanie Laucher, Melanie L Hart, Simon C Robson, Christa E Müller, Holger K Eltzschig
• Journal: Circulation (Circulation) Vol. 116 Issue 16 Pg. 1784-94 (Oct 16 2007) ISSN: 1524-4539 [Electronic] United States
• PMID: 17909107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Adenosine Monophosphate
• Apyrase
• CD39 antigen
• Adenosine

Topics

• Adenosine (metabolism)
• Adenosine Monophosphate (metabolism, pharmacology)
• Animals
• Antigens, CD (genetics, metabolism, pharmacology)
• Apyrase (genetics, metabolism, pharmacology)
• Disease Models, Animal
• Enzyme Induction
• Ischemic Preconditioning, Myocardial (methods)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Myocardial Infarction (metabolism, physiopathology, prevention & control)
• Myocardial Reperfusion Injury (metabolism, physiopathology, prevention & control)
• Myocardium (enzymology)