A2A adenosine receptors on bone marrow-derived cells protect liver from ischemia-reperfusion injury.
Activation of the A2A adenosine receptor (A(2A)R) 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(2A)R on bone marrow-derived cells. Bolus i.p. injection of the selective A2A 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 microg/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-gamma-inducible protein-10, IL-1alpha, IL-1-beta, IL-1Ralpha, IL-18, IL-6, and IFN-gamma), or histological criteria. ATL313, which is highly selective for the A(2A)R, 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(2A)R 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(2A)R on bone marrow-derived cells is primarily responsible for protecting the liver from reperfusion injury.
Day
Yuan-Ji
YJ
Cardiovascular Research Center, Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
Li
Yuesheng
Y
Rieger
Jayson M
JM
Ramos
Susan I
SI
Okusa
Mark D
MD
Linden
Joel
J
D058908:Adenosine A2 Receptor Agonists; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002678:Chimera; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology; D008099:Liver / Q000098:blood supply / Q000293:injuries* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011687:Purines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*
C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines; D011687:Purines; D043705:Receptor, Adenosine A2A; D000410:Alanine Transaminase