CD73-dependent adenosine generation and signaling through A2B adenosine receptors are essential for cardioprotection by ischemic preconditioning, reducing infarct sizes in mice.
Does CD73-dependent adenosine generation and A2B AR signaling reduce infarct size in mouse models of myocardial ischemia?
CD73-dependent adenosine generation and signaling through A2B adenosine receptors are crucial for cardioprotection by ischemic preconditioning, suggesting A2B AR agonists as potential therapy for myocardial ischemia.
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 (A1 AR, A2A AR, A2B AR, A3 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 A2B AR because it was selectively induced by ischemic preconditioning. Specifically, in situ ischemic preconditioning conferred cardioprotection in A1 AR-/-, A2A AR-/-, or A3 AR-/- mice but not in A2B AR-/- mice or in wild-type mice after inhibition of the A2B AR. Moreover, A2B 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 A2B AR for cardioprotection by ischemic preconditioning and suggests 5'-nucleotidase or A2B AR agonists as therapy for myocardial ischemia.
Eckle et al. (Tue,) conducted a other in Myocardial ischemia. Ischemic preconditioning, 5'-nucleotidase treatment, or A2B AR agonist vs. Wild-type or knockout controls was evaluated on Infarct size. CD73-dependent adenosine generation and signaling through A2B adenosine receptors are essential for cardioprotection by ischemic preconditioning, reducing infarct sizes in mice.