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(Circulation. 2006;114:2056-2064.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Myocardial Infarct–Sparing Effect of Adenosine A_2A Receptor Activation Is due to Its Action on CD4⁺ T Lymphocytes

Zequan Yang, MD, PhD; Yuan-Ji Day, MD, PhD; Marie-Claire Toufektsian, PhD; Yaqin Xu, MD, PhD; Susan I. Ramos, BS; Melissa A. Marshall, BS; Brent A. French, PhD; Joel Linden, PhD

From the Departments of Biomedical Engineering (Z.Y., M.-C.T., Y.X., B.A.F.), Medicine and Pharmacology (S.I.R., M.A.M., B.A.F., J.L.), and Surgery (Z.Y.), University of Virginia Health System, Charlottesville; and Department of Anesthesiology, Chang Gung University Hospital, Taipei, Taiwan (Y.-J.D.).

Correspondence to Dr Zequan Yang, Departments of Biomedical Engineering and Surgery, University of Virginia Health System, Box 800759, Charlottesville, VA 22903. E-mail zy6b{at}virginia.edu

Received July 1, 2006; revision received August 14, 2006; accepted September 1, 2006.

Background— We previously used adenosine A_2A receptor (A2AR) knockout (KO) mice and bone marrow transplantation to show that the infarct-sparing effect of A2AR activation at reperfusion is primarily due to effects on bone marrow–derived cells. In this study we show that CD4⁺ but not CD8⁺ T lymphocytes contribute to myocardial ischemia/reperfusion injury.

Method and Results— After a 45-minute occlusion of the left anterior descending coronary artery and reperfusion, T cells accumulate in the infarct zone within 2 minutes. Addition of 10 µg/kg of the A2AR agonist ATL146e 5 minutes before reperfusion produces a significant reduction in T-cell accumulation and a significant reduction in infarct size (percentage of risk area) measured at 24 hours. In Rag1 KO mice lacking mature lymphocytes, infarct size is significantly smaller than in C57BL/6 mice. Infarct size in Rag1 KO mice is increased to the level of B6 mice by adoptive transfer of 50 million CD4⁺ T lymphocytes derived from C57BL/6 or A2AR KO but not interferon- KO mice. ATL146e completely blocked the increase in infarct size in Rag1 KO mice reconstituted with B6 but not A2AR KO CD4⁺ T cells. The number of neutrophils in the reperfused heart at 24 hours after infarction correlated well with the number of lymphocytes and infarct size.

Conclusions— These results strongly suggest that the infarct-sparing effect of A2AR activation is primarily due to inhibition of CD4⁺ T-cell accumulation and activation in the reperfused heart.

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