Infarct-sparing effect of A2A-adenosine receptor activation is due primarily to its action on lymphocytes.
BACKGROUND
A2A-adenosine receptor (A2AAR) activation on reperfusion after ischemia reduces the size of myocardial infarction, but the mechanism of action has not been fully defined.


RESULTS
We created chimeric mice by bone marrow transplantation from A2AAR-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 microg/kg of a potent and selective agonist of A2AAR, 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 A2AAR-knockout mice or in mice treated with a selective A2AAR antagonist, ZM241385. ATL146e also reduced infarct size and myeloperoxidase in B6/B6 (donor/recipient) chimeras (P<0.05) but not in A2AAR-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 A2AAR 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.
Yang
Zequan
Z
Department of Biomedical Engineering, of Virginia Health System, Charlottesville 22903, USA. zy6b@virginia.edu
Day
Yuan-Ji
YJ
Toufektsian
Marie-Claire
MC
Ramos
Susan I
SI
Marshall
Melissa
M
Wang
Xin-Qun
XQ
French
Brent A
BA
Linden
Joel
J
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D007249:Inflammation / Q000517:prevention & control; D008214:Lymphocytes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy / Q000517:prevention & control*; D015425:Myocardial Reperfusion / Q000379:methods*; D009195:Peroxidase / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D018183:Transplantation Chimera
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D009195:Peroxidase