Adenosine A2A receptor activation reduces infarct size in the isolated, perfused mouse heart by inhibiting resident cardiac mast cell degranulation
Adenosine A2A receptor activation reduces infarct size in the isolated, perfused mouse heart by inhibiting resident cardiac mast cell degranulation
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DOI：
10.1152/ajpheart.495.2008
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发表时间：
2008-11-01
影响因子：
4.8
通讯作者：
Linden, Joel
中科院分区：
文献类型：
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作者：
Rork, Tyler H.;Wallace, Kori L.;Linden, Joel
Rork TH、Wallace KL、Kennedy DP、Matt MA、Lankford AR、Linden J.腺苷A(2A)受体激活通过抑制驻留的心脏肥大细胞脱颗粒，减少了离体鼠心脏的梗死范围。Am J Physiol心脏圈Physiol295：H1825-H1833,2008年；DOI：10.1152/ajpheart.495.2008-肥大细胞存在于心脏中，有助于心肌缺血后的再灌注损伤。由于A(2A)腺苷受体(A(2A)AR)的激活抑制了再灌注损伤，我们推测ATL146e(一种选择性的A(2A)AR激动剂)可能通过减少心肌肥大细胞脱颗粒而部分地保护心脏。从A(2A)AR(+/+)小鼠、A(2A)AR(+/+)小鼠、肥大细胞缺陷(Kit(W-sh/W-sh))小鼠以及将A(2A)AR(-/-)或A(2A)AR(-/-)小鼠的骨髓移植到辐射消融的A(2A)AR(+/+)小鼠的嵌合体小鼠中分离心脏。骨髓移植6周后，心肌肥大细胞重新植入90%的供体细胞。在缺血再灌流损伤的离体心中，ATL146e或CGS-21680(100nmol/L)分别将心肌梗死面积(危险面积百分比)从38+/-2%减少到24+/-2%和22+/-2%(P<；0.05)，并显著减少肥大细胞脱颗粒，以类胰蛋白酶释放到再灌流缓冲液中来衡量。这些变化在A(2A)AR(-/-)心脏和具有A(2A)AR(-/-)骨髓的嵌合小鼠的心脏中不存在。赋形剂处理的Kit(W-sh/W-sh)小鼠的IS(11+/-3%)低于WT小鼠(11+/-3%)，而ATL146e没有明显的保护作用(16+/-3%)。这些数据表明，在体外，缓冲灌流的心脏，肥大细胞脱颗粒有助于缺血再灌注损伤。此外，我们的数据表明，A(2A)AR的激活对心脏有保护作用，至少部分是通过减少常驻肥大细胞脱颗粒。
Rork TH, Wallace KL, Kennedy DP, Marshall MA, Lankford AR, Linden J. Adenosine A(2A) receptor activation reduces infarct size in the isolated, perfused mouse heart by inhibiting resident cardiac mast cell degranulation. Am J Physiol Heart Circ Physiol 295: H1825-H1833, 2008; doi:10.1152/ajpheart.495.2008.- Mast cells are found in the heart and contribute to reperfusion injury following myocardial ischemia. Since the activation of A(2A) adenosine receptors (A(2A)ARs) inhibits reperfusion injury, we hypothesized that ATL146e (a selective A(2A)AR agonist) might protect hearts in part by reducing cardiac mast cell degranulation. Hearts were isolated from five groups of congenic mice: A(2A)AR(+/+) mice, A(2A)AR(+/+) mice, mast cell-deficient (Kit(W-sh/W-sh)) mice, and chimeric mice prepared by transplanting bone marrow from A(2A)AR(-/-) or A(2A)AR(-/-) mice to radiation-ablated A(2A)AR(+/+) mice. Six weeks after bone marrow transplantation, cardiac mast cells were repopulated with >90% donor cells. In isolated, perfused hearts subjected to ischemia-reperfusion injury, ATL146e or CGS-21680 (100 nmol/l) decreased infarct size (IS; percent area at risk) from 38 +/- 2% to 24 +/- 2% and 22 +/- 2% in ATL146e- and CGS-21680-treated hearts, respectively (P < 0.05) and significantly reduced mast cell degranulation, measured as tryptase release into reperfusion buffer. These changes were absent in A(2A)AR(-/-) hearts and in hearts from chimeric mice with A(2A)AR(-/-) bone marrow. Vehicle-treated Kit(W-sh/W-sh) mice had lower IS (11 +/- 3%) than WT mice, and ATL146e had no significant protective effect (16 +/- 3%). These data suggest that in ex vivo, buffer-perfused hearts, mast cell degranulation contributes to ischemia-reperfusion injury. In addition, our data suggest that A(2A)AR activation is cardioprotective in the isolated heart, at least in part by attenuating resident mast cell degranulation.