Time Window Is Important for Adenosine Preventing Cold-induced Injury to the Endothelium
Time Window Is Important for Adenosine Preventing Cold-induced Injury to the Endothelium
复制标题
时间窗口对于腺苷预防寒冷引起的内皮损伤很重要
DOI：
10.1097/fjc.0000000000000489
复制
发表时间：
2017-06-01
影响因子：
3
通讯作者：
Ou, Jing-Song
中科院分区：
文献类型：
--
作者：
Li, Yan;Hu, Xiao-Xia;Ou, Jing-Song
摘要：冷心麻痹用于心脏手术过程中诱导心脏骤停。然而，此手术后内皮功能可能会受到损害。因此，模仿预处理效果的腺苷等干预措施可以最大限度地减少内皮损伤。在此，我们研究了腺苷是否可以预防寒冷引起的内皮损伤。用腺苷处理培养的人心脏微血管内皮细胞不同时间。使用二氨基荧光素-2 二乙酸 (DAF-2DA) 探针测量内皮一氧化氮合酶 (eNOS)、p38MAPK、ERK1/2 和 p70S6K6 的磷酸化和表达以及一氧化氮 (NO) 的产生。通过低温至 4°C 45 分钟模拟心脏直视手术期间冷心麻痹的条件，在人心脏微血管内皮细胞中诱导冷损伤。在基础条件下，腺苷在 5 分钟至 4 小时内刺激 NO 产生和丝氨酸 1177 处的 eNOS 磷酸化，并在 5 分钟至 6 小时内抑制苏氨酸 495 处的 eNOS 磷酸化，但仅在暴露 5 分钟后才增加 ERK1/2、p38MAPK 和 p70S6K 的磷酸化。寒冷引起的损伤抑制了一氧化氮的产生和不同酶的磷酸化。重要的是，腺苷可以防止低温损伤的这些影响。我们的数据表明，腺苷通过在早期时间点激活 ERK1/2、eNOS、p70S6K 和 p38MAPK 信号通路来防止内皮细胞低温损伤。这些发现还表明，给予腺苷或释放腺苷后5分钟是心脏手术期间心脏保护的重要时间窗口。
Abstract: Cold cardioplegia is used to induce heart arrest during cardiac surgery. However, endothelial function may be compromised after this procedure. Accordingly, interventions such as adenosine, that mimic the effects of preconditioning, may minimize endothelial injury. Herein, we investigated whether adenosine prevents cold-induced injury to the endothelium. Cultured human cardiac microvascular endothelial cells were treated with adenosine for different durations. Phosphorylation and expression of endothelial nitric oxide synthase (eNOS), p38MAPK, ERK1/2, and p70S6K6 were measured along with nitric oxide (NO) production using diaminofluorescein-2 diacetate (DAF-2DA) probe. Cold-induced injury by hypothermia to 4°C for 45 minutes to mimic conditions of cold cardioplegia during open heart surgery was induced in human cardiac microvascular endothelial cells. Under basal conditions, adenosine stimulated NO production, eNOS phosphorylation at serine 1177 from 5 minutes to 4 hours and inhibited eNOS phosphorylation at threonine 495 from 5 minutes to 6 hours, but increased phosphorylation of ERK1/2, p38MAPK, and p70S6K only after exposure for 5 minutes. Cold-induced injury inhibited NO production and the phosphorylation of the different enzymes. Importantly, adenosine prevented these effects of hypothermic injury. Our data demonstrated that adenosine prevents hypothermic injury to the endothelium by activating ERK1/2, eNOS, p70S6K, and p38MAPK signaling pathways at early time points. These findings also indicated that 5 minutes after administration of adenosine or release of adenosine is an important time window for cardioprotection during cardiac surgery.