Published Online
on March 12, 2007

A more recent version of this article appeared on March 27, 2007

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Submitted on October 13, 2006
Accepted on January 17, 2007

Cardioprotection by Ecto-5'-Nucleotidase (CD73) and A_2B Adenosine Receptors

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

From the Department of Anesthesiology and Intensive Care Medicine (T.E., D.K., K.U., H.K.E.), Department of Pharmacology and Toxicology (A.G., H.O.), and Institute of Brain Research (M.M.), Tübingen University Hospital, Tübingen, Germany; Bayer HealthCare AG, Wuppertal, Germany (T.K.); Institut de Recherches en Biologie Humaine et Moleculaire, Université Libre de Bruxelles, Brussels, Belgium (C.L.); Department of Pharmacology, Merck Research Laboratories, West Point, Pa (M.A.J.); and Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City (L.F.T.).

^* To whom correspondence should be addressed. E-mail: heltzschig{at}partners.org.

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, A_2AAR, A_2BAR, 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 A_2BAR because it was selectively induced by ischemic preconditioning. Specifically, in situ ischemic preconditioning conferred cardioprotection in A₁AR^-/-, A_2AAR^-/-, or A₃AR^-/- mice but not in A_2BAR^-/- mice or in wild-type mice after inhibition of the A_2BAR. Moreover, A_2BAR 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_2BAR for cardioprotection by ischemic preconditioning and suggests 5'-nucleotidase or A_2BAR agonists as therapy for myocardial ischemia.

Key words: adenosine • infarction • ischemia • reperfusion • nucleotidase

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