Published Online
on April 25, 2005

A more recent version of this article appeared on May 3, 2005

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Submitted on April 16, 2004
Revised on December 16, 2004
Accepted on December 21, 2004

Infarct-Sparing Effect of A_2A-Adenosine Receptor Activation Is Due Primarily to Its Action on Lymphocytes

Zequan Yang MD, PhD^*, Yuan-Ji Day MD, PhD, Marie-Claire Toufektsian PhD, Susan I. Ramos BS, Melissa Marshall BS, Xin-Qun Wang MS, Brent A. French PhD, and Joel Linden PhD

From the Department of Biomedical Engineering (Z.Y., M.-C.T., B.A.F.), Division of Cardiovascular Medicine (Z.Y., Y.-J.D., S.I.R., M.M., B.A.F., J.L.), and Department of Health Evaluation Sciences (X.-Q.W.), University of Virginia Health System, Charlottesville.

^* To whom correspondence should be addressed. E-mail: zy6b{at}virginia.edu.

Background--A_2A-adenosine receptor (A_2AAR) activation on reperfusion after ischemia reduces the size of myocardial infarction, but the mechanism of action has not been fully defined.

Methods and Results--We created chimeric mice by bone marrow transplantation from A_2AAR-knockout or green fluorescent donor mice to irradiated congenic C57BL/6 (B6) recipients. In the GFP chimeras, we were unable to detect green fluorescent-producing cells in the vascular endothelium, indicating that bone marrow-derived cells were not recruited to endothelium at appreciable levels after bone marrow transplantation and/or acute myocardial infarction. Injection of 5 or 10 µg/kg of a potent and selective agonist of A_2AAR, ATL146e, had no effect on hemodynamic parameters but reduced infarct size in B6 mice after 45 minutes of left anterior descending artery occlusion followed by 24 hours of reperfusion to 42.5±3.0% and 39.3±4.7% of risk region, respectively, compared with 61.0±2.3% in vehicle-treated B6 mice (P<0.05). Myocardial myeloperoxidase activity in the risk region measured at 4 hours after reperfusion was significantly reduced by ATL146e. The salutary effects of ATL146e were absent in A_2AAR-knockout mice or in mice treated with a selective A_2AAR antagonist, ZM241385. ATL146e also reduced infarct size and myeloperoxidase in B6/B6 (donor/recipient) chimeras (P<0.05) but not in A_2AAR-knockout/B6 chimeras. In immunocompromised Rag-1-KO mice, infarct size was significantly reduced compared with B6 mice but was not further reduced by ATL146e.

Conclusions--The results indicate that A_2AAR activation on bone marrow-derived cells, specifically T or B lymphocytes, is responsible for the infarct-sparing and antiinflammatory effects of ATL146e administered at the time of reperfusion after coronary occlusion.

Key words: adenosine • chimera • lymphocytes • myocardial infarction • receptors

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