Cardioprotection by ecto-5′-nucleotidase (CD73) and A2B adenosine receptors

Tobias Eckle, Thomas Krahn, Almut Grenz, David Köhler, Michel Mittelbronn, Catherine Ledent, Marlene A. Jacobson, Hartmut Osswald, Linda F. Thompson, Klaus Unertl, Holger K. Eltzschig*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

359 Citations (Scopus)

Abstract

BACKGROUND - Ecto-5′-nucleotidase (CD73)-dependent adenosine generation has been implicated in tissue protection during acute injury. Once generated, adenosine can activate cell-surface adenosine receptors (A1AR, A2AAR, A2BAR, A3AR). In the present study, we define the contribution of adenosine to cardioprotection by ischemic preconditioning. METHODS AND RESULTS - On the basis of observations of CD73 induction by ischemic preconditioning, we found that inhibition or targeted gene deletion of cd73 abolished infarct size-limiting effects. Moreover, 5′-nucleotidase treatment reconstituted cd73 mice and attenuated infarct sizes in wild-type mice. Transcriptional profiling of adenosine receptors suggested a contribution of A2BAR because it was selectively induced by ischemic preconditioning. Specifically, in situ ischemic preconditioning conferred cardioprotection in A1AR, A2AAR, or A3AR mice but not in A2BAR mice or in wild-type mice after inhibition of the A2BAR. Moreover, A2BAR agonist treatment significantly reduced infarct sizes after ischemia. CONCLUSIONS - Taken together, pharmacological and genetic evidence demonstrate the importance of CD73-dependent adenosine generation and signaling through A2BAR for cardioprotection by ischemic preconditioning and suggests 5′-nucleotidase or A2BAR agonists as therapy for myocardial ischemia.

Original languageEnglish
Pages (from-to)1581-1590
Number of pages10
JournalCirculation
Volume115
Issue number12
DOIs
Publication statusPublished - Mar 2007
Externally publishedYes

Keywords

  • Adenosine
  • Infarction
  • Ischemia
  • Nucleotidase
  • Reperfusion

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