Adora2b signaling on bone marrow derived cells dampens myocardial ischemia-reperfusion injury.
Adora2b signaling on bone marrow derived cells dampens myocardial ischemia-reperfusion injury.
复制标题
骨髓来源细胞上的 Adora2b 信号传导可抑制心肌缺血再灌注损伤。
DOI：
10.1097/aln.0b013e318255793c
复制
发表时间：
2012-06
期刊：
影响因子：
8.8
通讯作者：
Eckle T
中科院分区：
文献类型：
--
作者：
Koeppen M;Harter PN;Bonney S;Bonney M;Reithel S;Zachskorn C;Mittelbronn M;Eckle T
心脏缺血再灌注损伤（I/R）是心脏组织损伤的主要原因。腺苷信号传导抑制心脏I/R期间的炎症。在此，我们研究了腺苷A2b受体（Adora2b）在心脏I/R过程中对炎症细胞的作用。为了研究Adora2b在炎症细胞上的信号传导，我们将野生型（WT）骨髓（BM）移植到Adora2b −/−小鼠中，或将Adora2b −/− BM移植到WT小鼠中。为了研究多形核白细胞（PMN）的作用，用Adora2b激动剂处理嗜中性粒细胞耗尽的WT小鼠。治疗后，小鼠暴露于60分钟的心肌缺血和120分钟的再灌注。分别通过氯化三苯基四氮唑染色和ELISA测定细胞大小和肌钙蛋白-I水平。将WT-BM移植到Adora 2b-/-小鼠中，梗死面积减少了19 ± 4%，肌钙蛋白I减少了87.5 ± 25.3 ng/ml（平均值± SD，n = 6）。Adora2b −/− BM移植入WT小鼠后，梗死面积增加20 ± 3%，肌钙蛋白-I水平增加69.7 ± 17.9 ng/ml（平均值± SD，n = 6）。对再灌注心肌的研究显示，中性粒细胞为优势细胞类型。PMN耗竭或Adora2b激动剂治疗使梗死面积减少30 ± 11%或26 ± 13%（平均值± SD，n = 4），但两者联合治疗未显示进一步的心脏保护作用。细胞因子分析显示Adora2b −/−小鼠的心脏肿瘤坏死因子-α水平显著高于WT小鼠（39.3 ± 5.3 vs 7.5 ± 1.0 pg/mg蛋白，平均值± SD，n = 4）。对人活化的PMN的药理学研究显示Adora2b依赖性肿瘤坏死因子-α释放。Adora2b在骨髓来源细胞如中性粒细胞上的信号传导代表了心脏I/R期间的内源性心脏保护机制。我们的研究结果表明，心脏I/R期间Adora2b激动剂治疗减少了PMN的肿瘤坏死因子-α释放，从而抑制了组织损伤。
Cardiac ischemia-reperfusion injury (I/R) represents a major cause of cardiac tissue injury. Adenosine signaling dampens inflammation during cardiac I/R. Here, we investigated the role of the adenosine A2b-receptor (Adora2b) on inflammatory cells during cardiac I/R. To study Adora2b signaling on inflammatory cells, we transplanted wild-type (WT) bone marrow (BM) into Adora2b−/− mice or Adora2b−/− BM into WT mice. To study the role of polymorphonuclear leukocytes (PMNs), neutrophil-depleted WT mice were treated with an Adora2b agonist. Following treatments, mice were exposed to 60 min of myocardial ischemia and 120 min of reperfusion. Infarct sizes and Troponin-I levels were determined by triphenyltetrazolium chloride staining and ELISA, respectively. Transplantation of WT-BM into Adora2b−/− mice decreased infarct sizes by 19 ± 4% and Troponin-I by 87.5 ± 25.3 ng/ml (mean ± SD, n = 6). Transplantation of Adora2b−/− BM into WT mice increased infarct sizes by 20 ±3% and Troponin-I levels by 69.7 ± 17.9 ng/ml (mean ± SD, n = 6). Studies on the reperfused myocardium revealed PMNs as dominant cell type. PMN-depletion or Adora2b agonist treatment reduced infarct sizes by 30 ± 11% or 26 ± 13% (mean ± SD, n = 4), however the combination of both did not reveal further cardioprotection. Cytokine profiling showed significantly higher cardiac tumor-necrosis-factor-α levels in Adora2b−/− compared to WT mice (39.3 ± 5.3 vs. 7.5 ± 1.0 pg/mg protein, mean ± SD, n = 4). Pharmacological studies on human activated PMNs revealed an Adora2b dependent tumor-necrosis-factor-α release. Adora2b signaling on BM-derived cells such as PMNs represents an endogenous cardioprotective mechanism during cardiac I/R. Our findings suggest that Adora2b agonist treatment during cardiac I/R reduces tumor-necrosis-factor-α release of PMNs, thereby dampening tissue injury.