Heat shock transcription factor 1 protects against pressure overload-induced cardiac fibrosis via Smad3.
Heat shock transcription factor 1 protects against pressure overload-induced cardiac fibrosis via Smad3.
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热休克转录因子 1 通过 Smad3 防止压力超负荷诱导的心脏纤维化
DOI：
10.1007/s00109-016-1504-2
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Zou Y
中科院分区：
文献类型：
--
作者：
Zhou N;Ye Y;Wang X;Ma B;Wu J;Li L;Wang L;Wang DW;Zou Y
心肌纤维化表现为高刚度和低顺应性，是心力衰竭的主要危险因素。虽然热休克转录因子1（HSF 1）被确定为一种内在的心脏保护因子，但HSF 1在心脏纤维化中的作用仍不清楚。本研究旨在探讨HSF 1在压力超负荷性心肌纤维化中的作用及其机制。HSF1磷酸化显着下调，在横向主动脉缩窄（TAC）处理的小鼠心脏和机械拉伸心脏成纤维细胞（cFB）。对HSF1转基因（TG）小鼠、HSF1缺陷杂合子（KO）小鼠及其野生型同窝出生的小鼠进行4周的假手术或TAC手术。HSF1过表达显著减弱压力超负荷诱导的心脏纤维化和功能障碍。相反，HSF1 KO小鼠在TAC后显示恶化的纤维化反应和心功能障碍。此外，我们发现HSF1的过表达可以保护cFB对压力超负荷的纤维化反应。从机制上讲，我们观察到，与对照心脏相比，Smad家族成员3（Smad3）的磷酸化和核分布在HSF1过表达小鼠心脏中显著降低，而在TAC后的HSF1 KO小鼠心脏中则大大增加。在分离的小鼠心脏成纤维细胞和机械拉伸的cFB中发现Smad3磷酸化和核分布的类似改变。组成型活性Smad3阻断了cFB中HSF1的抗纤维化作用。此外，我们发现磷酸化的HSF1和Smad3的直接结合，这可以被机械应力抑制。最后，我谨指出，本研究首次证实了HSF1通过阻断Smad3的激活而作为一种新的心脏纤维化负调控因子。关键信息HSF1活性在纤维化心脏中降低。HSF1过表达减弱压力超负荷，HSF1的缺乏会恶化TAC后的纤维化反应和心功能障碍。HSF1通过直接作用抑制Smad3的磷酸化和核分布。活性Smad3阻断HSF 1的抗纤维化作用。
AbstractFibrotic cardiac muscle exhibits high stiffness and low compliance which are major risk factors of heart failure. Although heat shock transcription factor 1 (HSF1) was identified as an intrinsic cardioprotective factor, the role that HSF1 plays in cardiac fibrosis remains unclear. Our study aims to investigate the role of HSF1 in pressure overload-induced cardiac fibrosis and the underlying mechanism. HSF1 phosphorylation was significantly downregulated in transverse aortic constriction (TAC)-treated mouse hearts and mechanically stretched cardiac fibroblasts (cFBs). HSF1 transgenic (TG) mice, HSF1 deficient heterozygote (KO) mice, and their wild-type littermates were subjected to sham or TAC surgery for 4 weeks. HSF1 overexpression significantly attenuated pressure overload-induced cardiac fibrosis and dysfunction. Conversely, HSF1 KO mice showed deteriorated fibrotic response and cardiac dysfunction upon TAC. Moreover, we uncovered that overexpression of HSF1 protected against fibrotic response of cFBs to pressure overload. Mechanistically, we observed that the phosphorylation and the nuclear distribution of the Smad family member 3 (Smad3) were significantly decreased in HSF1-overexpressing mouse hearts, while being greatly increased in HSF1 KO mouse hearts upon TAC, compared to the control hearts, respectively. Similar alteration of Smad3 phosphorylation and nuclear distribution were found in isolated mouse cardiac fibroblasts and mechanically stretched cFBs. Constitutively active Smad3 blocked the anti-fibrotic effect of HSF1 in cFBs. Furthermore, we found a direct binding of phosphorylated HSF1 and Smad3, which can be suppressed by mechanical stress. In conclusion, the present study demonstrated for the first time that HSF1 acts as a novel negative regulator of cardiac fibrosis by blocking Smad3 activation.Key messagesHSF1 activity is decreased in fibrotic hearts.HSF1 overexpression attenuates pressure overload-induced cardiac fibrosis and dysfunction.Deficiency of HSF1 deteriorates fibrotic response and cardiac dysfunction upon TAC.HSF1 inhibits phosphorylation and nuclear distribution of Smad3 via direct binding to Smad3.Active Smad3 blocks the anti-fibrotic effect of HSF1.