The infarct-sparing effect of IB-MECA against myocardial ischemia/reperfusion injury in mice is mediated by sequential activation of adenosine A3 and A 2A receptors.
The infarct-sparing effect of IB-MECA against myocardial ischemia/reperfusion injury in mice is mediated by sequential activation of adenosine A3 and A 2A receptors.
复制标题
IB-MECA 对小鼠心肌缺血/再灌注损伤的梗塞保留作用是通过腺苷 A3 和 A 2A 受体的连续激活介导的。
DOI：
10.1007/s00395-015-0473-x
复制
发表时间：
2015
影响因子：
9.5
通讯作者：
Yang,Zequan
中科院分区：
文献类型：
--
作者：
Tian,Yikui;Marshall,Melissa;French,BrentA;Linden,Joel;Yang,Zequan
关于 A3 腺苷受体 (A3AR) 在心肌梗死后再灌注期间介导心脏保护中的作用，存在相互矛盾的结果。我们假设 A3AR 激动剂 IB-MECA 产生心脏保护作用可能涉及其他腺苷受体亚型的激活。 C57Bl/6 (B6)、A3AR KO、A2AAR KO 和 A2AAR KO/WT 骨髓嵌合小鼠被分配到 12 组，进行血流动力学研究或 45 分钟的 LAD 闭塞和 60 分钟的再灌注。再灌注前 5 分钟通过静脉推注施用 IB-MECA（100 μg/kg）或载体。放射性配体结合测定表明，IB-MECA 对小鼠 A3AR 具有高亲和力 (Ki= 0.17 ± 0.05 nM)，但也能以较低的亲和力与 A1AR (9.0 ± 2.4 nM) 或 A2AAR (56.5 ± 10.2 nM) 结合。 IB-MECA 引起双相血流动力学变化，这种变化在 A3AR KO 小鼠中完全不存在，并通过 A2AAR 阻断或缺失而改变。 IB-MECA 刺激组胺释放，增加心率，并显着降低 B6 小鼠中 IF 大小，从危险区域的 61.5 ± 1.4 降低至 48.6 ± 2.4 %（RR；降低 21 %，p < 0.05），但在 A3AR KO 小鼠中则不然。与 B6 相比，A3AR KO 小鼠的 IF 大小显着减小 (p< 0.05)。在 B6/B6 骨髓嵌合体中，IB-MECA 导致 IF 大小减少 47%（从 47.3 ± 3.9 到 24.7 ± 4.5，p < 0.05）。然而，在 A2AARKO/B6 小鼠中没有观察到 IB-MECA 的显着心脏保护作用，这些小鼠仅在骨髓来源的细胞上缺乏 A2AAR。 A3AR 的激活会诱导双相血流动力学反应，该反应部分是由 A2AAR 的激活介导的。 IB-MECA 的心脏保护作用是由于骨髓来源细胞中 A3AR 的初始激活，随后 A2AAR 的激活。
Conflicting results exist regarding the role of A3adenosine receptors (A3ARs) in mediating cardioprotection during reperfusion following myocardial infarction. We hypothesized that the effects of the A3AR agonist IB-MECA to produce cardioprotection might involve activation of other adenosine receptor subtypes. C57Bl/6 (B6), A3AR KO, A2AAR KO, and A2AAR KO/WT bone marrow chimeric mice were assigned to 12 groups undergoing either hemodynamic studies or 45 min of LAD occlusion and 60 min of reperfusion. IB-MECA (100 μg/kg) or vehicle was administered by iv bolus 5 min before reperfusion. Radioligand binding assays showed that IB-MECA has high affinity for the mouse A3AR (Ki= 0.17 ± 0.05 nM), but also can bind with lower affinity to the A1AR (9.0 ± 2.4nM) or the A2AAR (56.5 ± 10.2nM). IB-MECA caused bi-phasic hemodynamic changes, which were completely absent in A3AR KO mice and were modified by A2AAR blockade or deletion. IB-MECA stimulated histamine release, increased heart rate, and significantly reduced IF size in B6 mice from 61.5 ± 1.4 to 48.6 ± 2.4 % of risk region (RR; 21 % reduction,p< 0.05) but not in A3AR KO mice. Compared to B6, A3AR KO mice had significantly reduced IF size (p< 0.05). In B6/B6 bone marrow chimeras, IB-MECA caused a 47 % reduction of IF size (from 47.3 ± 3.9 to 24.7 ± 4.5,p< 0.05). However, no significant cardioprotective effect of IB-MECA was observed in A2AARKO/B6 mice, which lacked A2AARs only on their bone marrow-derived cells. Activation of A3ARs induces a bi-phasic hemodynamic response, which is partially mediated by activation of A2AARs. The cardioprotective effect of IB-MECA is due to the initial activation of A3AR followed by activation of A2AARs in bone marrow-derived cells.