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 (A1 AR, A2A AR, A2B AR, A3 AR). In the present study, we define the contribution of adenosine to cardioprotection by ischemic preconditioning.


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
Tobias
T
Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Hoppe-Seyler-Str 3, D-72076 Tübingen, Germany.
Krahn
Thomas
T
Grenz
Almut
A
Köhler
David
D
Mittelbronn
Michel
M
Ledent
Catherine
C
Jacobson
Marlene A
MA
Osswald
Hartmut
H
Thompson
Linda F
LF
Unertl
Klaus
K
Eltzschig
Holger K
HK
D015720:5'-Nucleotidase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000241:Adenosine / Q000502:physiology*; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism; D009504:Neutrophils; D043704:Receptor, Adenosine A2B / Q000096:biosynthesis / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D014970:Xanthines / Q000494:pharmacology / Q000633:toxicity
C518874:1-propyl-8-(4-sulfophenyl)xanthine; D000631:Aminopyridines; C518875:BAY 60-6583; D002316:Cardiotonic Agents; D043704:Receptor, Adenosine A2B; D014970:Xanthines; D015720:5'-Nucleotidase; D000241:Adenosine