A2A-adenosine receptor activation with ATL146e reduced infarct size to 42.5% and 39.3% of the risk region at 5 and 10 microg/kg, respectively, compared with 61.0% in vehicle-treated mice (P<0.05).
Does ATL146e reduce infarct size in mouse models of myocardial ischemia-reperfusion injury?
A2A-adenosine receptor activation reduces myocardial infarct size and inflammation primarily through its action on bone marrow-derived lymphocytes.
Absolute Event Rate: 42.5% vs 61%
p-value: p=<0.05
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. METHODS AND 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 et al. (Tue,) conducted a other in Myocardial infarction. ATL146e vs. Vehicle was evaluated on Infarct size as a percentage of risk region (p=<0.05). A2A-adenosine receptor activation with ATL146e reduced infarct size to 42.5% and 39.3% of the risk region at 5 and 10 microg/kg, respectively, compared with 61.0% in vehicle-treated mice (P<0.05).