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(Circulation. 2005;111:2190-2197.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

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; 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.

Correspondence to Dr Zequan Yang, Department of Biomedical Engineering, University of Virginia Health System, Box 800759, MR5 Bldg, 415 Lane Rd, Charlottesville, VA 22903. E-mail zy6b{at}virginia.edu

Received April 16, 2004; revision received December 16, 2004; accepted December 21, 2004.

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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