Inhibition of p38 MAPK During Ischemia, But Not Reperfusion, Effectively Attenuates Fatal Arrhythmia in Ischemia/Reperfusion Heart
Inhibition of p38 MAPK During Ischemia, But Not Reperfusion, Effectively Attenuates Fatal Arrhythmia in Ischemia/Reperfusion Heart
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DOI：
10.1097/fjc.0b013e318279b7b1
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发表时间：
2013-02-01
影响因子：
3
通讯作者：
Chattipakorn, Nipon
中科院分区：
文献类型：
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作者：
Surinkaew, Sirirat;Kumphune, Sarawut;Chattipakorn, Nipon
丝裂原激活蛋白激酶（MAPK）在缺血/再灌注（I/R）损伤中发挥重要作用。先前的证据表明，缺血前抑制 p38 MAPK 具有心脏保护作用。然而，缺血或再灌注期间 p38 MAPK 抑制是否能提供心脏保护作用尚不清楚。我们测试了以下假设：在 I/R 期间的不同时间抑制 p38 MAPK 可保护心脏免受心律失常、减少梗塞面积并减轻心室功能障碍。成年 Wistar 大鼠接受 30 分钟的左冠状动脉前降支闭塞，然后进行 120 分钟的再灌注。 p38 MAPK 抑制剂 SB203580 在左冠状动脉前降支闭塞前、缺血期间或再灌注开始时静脉注射。结果显示，在缺血之前或期间（但不在再灌注开始时）给予SB203580，可降低室性心动过速/心室颤动（VT/VF）发生率和热休克蛋白27磷酸化，并增加连接蛋白43磷酸化。所有 SB203580 治疗的大鼠中，梗塞面积和细胞色素 c 水平均有所下降，但总 Bax/Bcl-2 表达没有改变。仅SB203580预处理的大鼠的心室功能得到改善。这些发现表明，p38 MAPK 抑制相对于缺血发作的时间是治疗效果的重要决定因素。
The mitogen-activated protein kinases (MAPKs) play an important role in ischemia/reperfusion (I/R) injury. Previous evidence suggests that p38 MAPK inhibition before ischemia is cardioprotective. However, whether p38 MAPK inhibition during ischemia or reperfusion provides cardioprotection is not well known. We tested the hypothesis that p38 MAPK inhibition at different times during I/R protects the heart from arrhythmias, reduces the infarct size, and attenuates ventricular dysfunction. Adult Wistar rats were subject to a 30-minute left anterior descending coronary artery occlusion, followed by a 120-minute reperfusion. A p38 MAPK inhibitor, SB203580, was given intravenously before left anterior descending coronary artery occlusion, during ischemia, or at the onset of reperfusion. The results showed that SB203580 given either before or during ischemia, but not at the onset of reperfusion, decreased the ventricular tachycardia/ventricular fibrillation (VT/VF) incidence and heat shock protein 27 phosphorylation, and increased connexin 43 phosphorylation. The infarct size and cytochrome c level was decreased in all SB203580-treated rats, without the alteration of the total Bax/Bcl-2 expression. The ventricular function was improved only in SB203580-pretreated rats. These findings suggest that timing of p38 MAPK inhibition with respect to onset of ischemia is an important determinant of therapeutic efficacy.