Upregulation of heat shock transcription factor 1 plays a critical role in adaptive cardiac hypertrophy
Upregulation of heat shock transcription factor 1 plays a critical role in adaptive cardiac hypertrophy
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DOI：
10.1161/01.res.0000252345.80198.97
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发表时间：
2006-12-08
影响因子：
20.1
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Sakamoto, Masaya;Minamino, Tohru;Komuro, Issei
有报道称，运动诱发的心肌肥大比压力超负荷诱发的心肌肥大预后更好。运动性心肌肥厚与心肌纤维化程度低、收缩功能好有关，提示运动性心肌肥厚可能存在适应性机制。在这里，我们发现了热休克转录因子1（HSF 1），热休克蛋白的重要转录因子，在心脏肥大的适应性机制中的关键作用。我们用基因芯片技术检测了运动性心肌肥厚模型心肌中8800个基因的表达，并与压力超负荷性心肌肥厚进行了比较。HSF1及其靶分子热休克蛋白的表达在运动心脏中显著上调，但在慢性压力超负荷中没有。组成性激活心脏中的HSF 1显着改善心肌细胞的死亡和心脏纤维化，从而防止心脏功能障碍以及慢性压力超负荷诱导的肥大。相反，心脏中HSF1活性的降低促进了对运动的心功能障碍，运动是一种通常导致适应性肥大并保留收缩功能的负荷。同样地，当HSF 1激活被抑制时，心脏功能从压力超负荷的早期阶段显著受损。这些结果表明，HSF 1在适应性和适应不良性肥大之间的过渡中起着关键作用。
Exercise-induced cardiac hypertrophy has been reported to have better prognosis than pressure overload-induced cardiac hypertrophy. Cardiac hypertrophy induced by exercise was associated with less cardiac fibrosis and better systolic function, suggesting that the adaptive mechanisms may exist in exercise-induced hypertrophy. Here, we showed a critical role of heat shock transcription factor 1 (HSF1), an important transcription factor for heat shock proteins, in the adaptive mechanism of cardiac hypertrophy. We examined expression of 8800 genes in the heart of exercise-induced hypertrophy model using DNA chip technique and compared with pressure overload-induced hypertrophy. Expression of HSF1 and its target molecule heat shock proteins was significantly upregulated in the heart by exercise but not by chronic pressure overload. Constitutive activation of HSF1 in the heart significantly ameliorated death of cardiomyocytes and cardiac fibrosis and thereby prevented cardiac dysfunction as well as hypertrophy induced by chronic pressure overload. Conversely, decreased activity of HSF1 in the heart promoted cardiac dysfunction in response to exercise, a load that normally leads to adaptive hypertrophy with preserved systolic function. Likewise, cardiac function was significantly impaired from the early phase of pressure overload, when HSF1 activation was inhibited. These results suggest that HSF1 plays a critical role in the transition between adaptive and maladaptive hypertrophy.