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

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 (A(1)AR, A(2A)AR, A(2B)AR, A(3)AR). 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 A(2B)AR because it was selectively induced by ischemic preconditioning. Specifically, in situ ischemic preconditioning conferred cardioprotection in A(1)AR(-/-), A(2A)AR(-/-), or A(3)AR(-/-) mice but not in A(2B)AR(-/-) mice or in wild-type mice after inhibition of the A(2B)AR. Moreover, A(2B)AR 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 A(2B)AR for cardioprotection by ischemic preconditioning and suggests 5'-nucleotidase or A(2B)AR agonists as therapy for myocardial ischemia.