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(Circulation. 2007;115:1581-1590.)
© 2007 American Heart Association, Inc.
Molecular Cardiology |
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.).
Correspondence to Holger K. Eltzschig, MD, PhD, Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Hoppe-Seyler-Str 3, D-72076 Tübingen, Germany. E-mail heltzschig{at}partners.org
Received October 13, 2006; accepted January 17, 2007.
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, A2AAR, A2BAR, 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 A2BAR because it was selectively induced by ischemic preconditioning. Specifically, in situ ischemic preconditioning conferred cardioprotection in A1AR/, A2AAR/, or A3AR/ mice but not in A2BAR/ mice or in wild-type mice after inhibition of the A2BAR. Moreover, A2BAR 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 A2BAR for cardioprotection by ischemic preconditioning and suggests 5'-nucleotidase or A2BAR agonists as therapy for myocardial ischemia.
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