Journal
CIRCULATION
Volume 111, Issue 17, Pages 2190-2197Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.CIR.0000163586.62253.A5
Keywords
adenosine; chimera; lymphocytes; myocardial infarction; receptors
Funding
- NHLBI NIH HHS [R01-HL-37942, R01-HL-69494] Funding Source: Medline
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Background-A(2A)-adenosine receptor (A(2A)AR) 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(2A)AR-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 mu g/kg of a potent and selective agonist of A(2A)AR, 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(2A)AR-knockout mice or in mice treated with a selective A(2A)AR antagonist, ZM241385. ATL146e also reduced infarct size and myeloperoxidase in B6/B6 (donor/recipient) chimeras (P < 0.05) but not in A(2A)AR-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(2A)AR 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.
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