Cardioprotection by ecto-5'-nucleotidase (CD73) and A2B adenosine receptors.

Abstract

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: Tobias Eckle, Thomas Krahn, Almut Grenz, David Köhler, Michel Mittelbronn, Catherine Ledent, Marlene A Jacobson, Hartmut Osswald, Linda F Thompson, Klaus Unertl, Holger K Eltzschig
• Journal: Circulation (Circulation) Vol. 115 Issue 12 Pg. 1581-90 (Mar 27 2007) ISSN: 1524-4539 [Electronic] United States
• PMID: 17353435 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1-propyl-8-(4-sulfophenyl)xanthine
• Aminopyridines
• BAY 60-6583
• Cardiotonic Agents
• Receptor, Adenosine A2B
• Xanthines
• 5'-Nucleotidase
• Adenosine

Topics

• 5'-Nucleotidase (deficiency, genetics, physiology)
• Adenosine (physiology)
• Aminopyridines (pharmacology, therapeutic use)
• Animals
• Cardiotonic Agents (pharmacology, therapeutic use)
• Cell Hypoxia (genetics)
• Drug Evaluation, Preclinical
• Extracellular Fluid (metabolism)
• Female
• Ischemic Preconditioning, Myocardial
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Infarction (pathology)
• Myocardial Ischemia (drug therapy, metabolism)
• Neutrophils
• Receptor, Adenosine A2B (biosynthesis, deficiency, drug effects, genetics, physiology)
• Up-Regulation
• Xanthines (pharmacology, toxicity)