Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

[摘要] Adenosine increases coronary flow mainly through the activation of A_2A and A_2B adenosine receptors (ARs). However, the mechanisms for the regulation of coronary flow are not fully understood. We previously demonstrated that adenosine-induced increase in coronary flow is in part through NADPH oxidase (Nox) activation, which is independent of activation of either A₁ or A₃ARs. In this study, we hypothesize that adenosine-mediated increase in coronary flow through Nox activation depends on A_2A but not A_2BARs. Functional studies were conducted using isolated Langendorff-perfused mouse hearts. Hydrogen peroxide (H₂O₂) production was measured in isolated coronary arteries from WT, A_2AAR knockout (KO), and A_2BAR KO mice using dichlorofluorescein immunofluorescence. Adenosine-induced concentration-dependent increase in coronary flow was attenuated by the specific Nox2 inhibitor gp91 ds-tat or reactive oxygen species (ROS) scavenger EUK134 in both WT and A_2B but not A_2AAR KO isolated hearts. Similarly, the A_2AAR selective agonist CGS-21680-induced increase in coronary flow was significantly blunted by Nox2 inhibition in both WT and A_2BAR KO, while the A_2BAR selective agonist BAY 60-6583-induced increase in coronary flow was not affected by Nox2 inhibition in WT. In intact isolated coronary arteries, adenosine-induced (10 μM) increase in H₂O₂ formation in both WT and A_2BAR KO mice was attenuated by Nox2 inhibition, whereas adenosine failed to increase H₂O₂ production in A_2AAR KO mice. In conclusion, adenosine-induced increase in coronary flow is partially mediated by Nox2-derived H₂O₂, which critically depends upon the presence of A_2AAR.

[学科分类] 分子生物学，细胞生物学和基因

[关键词] Coronary flow