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.
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.
Authors: Ming Cai; Zachary M Huttinger; Heng He; Weizhi Zhang; Feng Li; Lauren A Goodman; Debra G Wheeler; Lawrence J Druhan; Jay L Zweier; Karen M Dwyer; Guanglong He; Anthony J F d'Apice; Simon C Robson; Peter J Cowan; Richard J Gumina Journal: J Mol Cell Cardiol Date: 2011-09-12 Impact factor: 5.000
Authors: Debra G Wheeler; Matthew E Joseph; Shouvik D Mahamud; William L Aurand; Peter J Mohler; Vincent J Pompili; Karen M Dwyer; Mark B Nottle; Sharon J Harrison; Anthony J F d'Apice; Simon C Robson; Peter J Cowan; Richard J Gumina Journal: J Mol Cell Cardiol Date: 2012-01-12 Impact factor: 5.000
Authors: Hiroki Tsukamoto; Petya Chernogorova; Korcan Ayata; Ulrike V Gerlach; Ankur Rughani; Jerry W Ritchey; Jayanthi Ganesan; Marie Follo; Robert Zeiser; Linda F Thompson; Marco Idzko Journal: Blood Date: 2012-01-18 Impact factor: 22.113