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A_2A Adenosine Receptors on Bone Marrow-Derived Cells Protect Liver from Ischemia-Reperfusion Injury¹

Yuan-Ji Day^*,, Yuesheng Li, Jayson M. Rieger, Susan I. Ramos^*, Mark D. Okusa and Joel Linden^2,*,

^* Cardiovascular Research Center, Departments of Molecular Physiology and Biological Physics and Medicine, University of Virginia, Charlottesville, VA 22908; and Adenosine Therapeutics, LLC, Charlottesville, VA 22911

Activation of the A_2A adenosine receptor (A_2AR) during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In this study, we used bone marrow transplantation (BMT) to create chimeric mice that either selectively lack or selectively express the A_2AR on bone marrow-derived cells. Bolus i.p. injection of the selective A_2A agonist, 4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid methyl ester (ATL313; 3 µg/kg), at the time of reperfusion protects wild-type (wt) mice from liver ischemia-reperfusion injury. ATL313 also protects wt/wt (donor/recipient BMT mouse chimera) and wt/knockout chimera but produces modest protection of knockout/wt chimera as assessed by alanine aminotransferase activity, induction of cytokine transcripts (RANTES, IFN--inducible protein-10, IL-1, IL-1-, IL-1R, IL-18, IL-6, and IFN-), or histological criteria. ATL313, which is highly selective for the A_2AR, produces more liver protection of chimeric BMT mice than 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester, which is rapidly metabolized in mice to produce 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid, which has similar affinity for the A_2AR and the proinflammatory A₃ adenosine receptor. GFP chimera mice were created to show that vascular endothelial cells in the injured liver do not account for liver protection because they are not derived by transdifferentiation of bone marrow precursors. The data suggest that activation of the A_2AR on bone marrow-derived cells is primarily responsible for protecting the liver from reperfusion injury.

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