Association of Stat3 with HSF1 plays a critical role in G-CSF-induced cardio-protection against ischemia/reperfusion injury
Association of Stat3 with HSF1 plays a critical role in G-CSF-induced cardio-protection against ischemia/reperfusion injury
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Stat3 与 HSF1 的关联在 G-CSF 诱导的缺血/再灌注损伤心脏保护中发挥关键作用
DOI：
10.1016/j.yjmcc.2012.02.011
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发表时间：
2012-06-01
影响因子：
5
通讯作者：
Zou, Yunzeng
中科院分区：
文献类型：
--
作者：
Ma, Hong;Gong, Hui;Zou, Yunzeng
粒细胞集落刺激因子(G-CSF)通过激活JAK2/STAT3通路发挥心脏保护作用，但其作用机制尚不清楚。热休克转录因子1(HSF1)是心肌细胞中一种明确的内源性保护蛋白，在应激条件下可能与STAT家族相互作用。我们推测G-CSF可以通过HSF1和STAT3的联合作用来诱导心肌保护作用。为了验证这一假设，我们用HSF1基因敲除(KO)小鼠和野生型(WT)小鼠建立心脏I/R损伤模型，结扎左冠状动脉前降支(LAD)30min，然后解除结扎24 h，这些小鼠在手术前3d皮下注射G-CSF(100 mg/kg/d)或皮下注射赋形剂。不出所料，G-CSF对WT小鼠I/R损伤有明显的心脏保护作用，表现为与赋形剂治疗组相比，射血分数(EF%)增加，左室舒张末压(LVEDP)降低，dp/dt值增加，梗塞面积缩小。然而，在HSF1-KO小鼠中，G-CSF诱导的这些心脏保护作用大大减弱。由于体内和体外HSF1的缺失，G-CSF对氧化应激诱导的心肌细胞凋亡的抑制作用也消失了。此外，G-CSF增加了STAT3的磷酸化和与HSF1的结合，从而增强了HSF1的转录活性。药物对STAT3或HSF1的抑制可抑制G-CSF诱导的这两种蛋白的结合和对心肌细胞的抗凋亡作用。我们的数据提示G-CSF刺激STAT3的磷酸化和与HSF1的结合，从而增强HSF1的转录活性，从而对I/R损伤产生心脏保护作用。皇冠版权所有(C)2012由爱思唯尔有限公司出版。保留所有权利。
Granulocyte colony-stimulating factor (G-CSF) has been shown to be cardio-protective against ischemia through activating Jak2/Stat3 pathway, however, the mechanism is unclear. Heat shock transcription factor 1 (HSF1), a definite endogenous protective protein in cardiomyocytes, may interact with Stat family under stress conditions. We hypothesized that G-CSF could induce cardio-protection against ischemia/reperfusion (I/R) through association of HSF1 with Stat3. To test the hypothesis, we built cardiac I/R injury model with HSF1 knockout (KO) mice and wild type (WT) mice by occlusion of the left anterior descending (LAD) coronary artery for 30 min and subsequent release of the occlusion for 24 h. These mice were administered with G-CSF (100 mu g/kg/day) or vehicle subcutaneously for 3 days before surgery. As expected, G-CSF induced significant cardio-protections against I/R injury, characterized by higher ejection fraction (EF%), lower left ventricular end diastolic pressure (LVEDP), increased dp/dt value and decreased infarct area as compared with the vehicle treatment in WT mice. In HSF1-KO mice, however, these cardio-protections induced by G-CSF were greatly attenuated. Inhibition of oxidative stress-induced cardiomyocyte apoptosis by G-CSF also disappeared due to the deficiency of HSF1 in vitro and in vivo. Furthermore, G-CSF increased the phosphorylation and the association of Stat3 with HSF1, which enhanced transcriptional activity of HSF1. Inhibition of either Stat3 or HSF1 by pharmacological agents suppressed G-CSF-induced association of the two proteins and antiapoptotic effect on cardiomyocytes. Our data suggest that G-CSF stimulates phosphorylation and association of Stat3 with HSF1 and therefore enhances transcriptional activity of HSF1, leading to the cardio-protection against I/R injury. Crown Copyright (C) 2012 Published by Elsevier Ltd. All rights reserved.