Cardioprotection by Ecto-5′-Nucleotidase (CD73) and A 2B Adenosine Receptors

• DOI: 10.1161/circulationaha.106.669697
• Publication Date: 2007-03-13T06:24:23Z
• 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
• Keywords: Male; Adenosine; Aminopyridines -- therapeutic use; Neutrophils; Myocardial Ischemia -- metabolism; Drug Evaluation, Preclinical; Myocardial Infarction; Myocardial Ischemia; Aminopyridines; Extracellular Fluid -- metabolism; Inbred C57BL; Adenosine A2B -- physiology; 5'-Nucleotidase -- physiology; Mice; Ischemia; Ischemic Preconditioning; 5'-Nucleotidase; Myocardial Infarction -- pathology; Mice, Knockout; 0303 health sciences; Sciences bio-médicales et agricoles; Preclinical; Cell Hypoxia; Up-Regulation; Myocardial Ischemia -- drug therapy; Infarction; Ischemic Preconditioning, Myocardial; Female; Receptor; Cardiotonic Agents; Knockout; Xanthines -- pharmacology; Receptor, Adenosine A2B; Adenosine A2B -- biosynthesis; 03 medical and health sciences; Cardiotonic Agents -- pharmacology; 5'-Nucleotidase -- genetics; Nucleotidase; Xanthines -- toxicity; Myocardial; Animals; Aminopyridines -- pharmacology; Adenosine A2B -- drug effects; Adenosine A2B -- deficiency; Adenosine A2B -- genetics; Cardiotonic Agents -- therapeutic use; Extracellular Fluid; Mice, Inbred C57BL; Adenosine -- physiology; Xanthines; Reperfusion; Drug Evaluation; Cell Hypoxia -- genetics; 5'-Nucleotidase -- deficiency

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 (A 1 AR, A 2A AR, A 2B AR, A 3 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 A 2B AR because it was selectively induced by ischemic preconditioning. Specifically, in situ ischemic preconditioning conferred cardioprotection in

A 1 AR −/−

,

A 2A AR −/−

, or

A 3 AR −/−

mice but not in

A 2B AR −/−

mice or in wild-type mice after inhibition of the A 2B AR. Moreover, A 2B 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 A 2B AR for cardioprotection by ischemic preconditioning and suggests 5′-nucleotidase or A 2B AR agonists as therapy for myocardial ischemia.