The critical role of Sestrin 1 in regulating the proliferation of cardiac fibroblasts.
The critical role of Sestrin 1 in regulating the proliferation of cardiac fibroblasts.
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DOI：
10.1016/j.abb.2013.11.011
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发表时间：
2014-01
影响因子：
3.9
通讯作者：
Gang Sun;Ruicong Xue;Fengjuan Yao;Dan Liu;Huiling Huang;Cong Chen;Yanhui Li;J. Zeng;
中科院分区：
文献类型：
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作者：
Gang Sun;Ruicong Xue;Fengjuan Yao;Dan Liu;Huiling Huang;Cong Chen;Yanhui Li;J. Zeng;
心脏成纤维细胞的增殖在心脏纤维化的发展中起关键作用。Sestrin 1作为一种抗氧化剂，在氧化应激诱导的细胞增殖和损伤的调节中发挥着多种作用。然而，关于Sestrin 1对心脏成纤维细胞增殖的影响知之甚少。在本研究中，通过siRNA敲低Sestrin 1，我们调查了Sestrin 1对心脏成纤维细胞增殖的影响。下调Sestrin 1促进Ang II诱导的心脏成纤维细胞增殖，导致DNA合成和胶原蛋白产生增加。此外，在缺乏血管紧张素II的情况下，检测到与基础条件相似的表型，其中Sestrin 1沉默。进一步分析促增殖信号发现，Sestrin 1的下调可显著激活ERK 1/2和mTOR，同时下调Sestrin 1还可促进I型胶原和CTGF的表达，这两种蛋白在心肌纤维化中起重要作用。与Sestrin 1的抗氧化特性一致，我们确定了由Sestrin 1的沉默诱导的增殖伴随着活性氧（ROS）的显著增强的产生。然而，减少活性氧的NAC，一种有效的抗氧化剂，只能部分抑制促增殖作用的Sestrin 1下调。因此，我们的研究表明，Sestrin 1在心脏成纤维细胞的增殖中起着重要作用，这种作用可能部分由氧化应激降低介导。
The proliferation of cardiac fibroblasts is pivotal in the development of cardiac fibrosis. Sestrin 1, which functions as antioxidant, plays diverse roles in the regulation of proliferation and cellular injury that is induced by oxidative stress. However, little is known regarding the impact of Sestrin 1 on the proliferation of cardiac fibroblasts. In the present study, with knockdown of Sestrin 1 by siRNA, we surveyed the effect of Sestrin 1 on cardiac fibroblast proliferation. Downregulation of Sestrin 1 promotes Ang II-induced proliferation of cardiac fibroblasts, leading to increased DNA synthesis and collagen production. Moreover, in the absence of Ang II, a similar phenotype to the basal condition was detected with silencing of Sestrin 1. Further analysis of the pro-proliferating signals revealed that knockdown of Sestrin 1 significantly activated ERK1/2 and mTOR, meanwhile, downregulation of Sestrin 1 also enhanced the expression of collagen type I and CTGF, which play important role in the cardiac fibrosis. Consistent with the antioxidant property of Sestrin 1, we determined that the proliferation induced by silence of Sestrin 1 was accompanied by a remarkably enhanced production of reactive oxygen species (ROS). However, diminishing ROS by NAC, a potent antioxidant, could only partly repress the pro-proliferative effect of Sestrin 1-downregulation. Consequently, our study demonstrated that Sestrin 1 plays an important role in the proliferation of cardiac fibroblasts, and the effect could be partly mediated by decreased oxidative stress.