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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. 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.

Pubmed ID: 17353435

Authors

  • Eckle T
  • Krahn T
  • Grenz A
  • K√∂hler D
  • Mittelbronn M
  • Ledent C
  • Jacobson MA
  • Osswald H
  • Thompson LF
  • Unertl K
  • Eltzschig HK

Journal

Circulation

Publication Data

March 27, 2007

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI18220

Mesh Terms

  • 5'-Nucleotidase
  • Adenosine
  • Aminopyridines
  • Animals
  • Cardiotonic Agents
  • Cell Hypoxia
  • Drug Evaluation, Preclinical
  • Extracellular Fluid
  • Female
  • Ischemic Preconditioning, Myocardial
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction
  • Myocardial Ischemia
  • Neutrophils
  • Receptor, Adenosine A2B
  • Up-Regulation
  • Xanthines