FoxO1 mediates TGF-beta1-dependent cardiac myofibroblast differentiation
FoxO1 mediates TGF-beta1-dependent cardiac myofibroblast differentiation
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fox01介导tgf - β - 1依赖性心肌成纤维细胞分化
DOI：
10.1016/j.bbamcr.2015.10.019
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发表时间：
2016-01-01
影响因子：
5.1
通讯作者：
Diaz-Araya, Guillermo
中科院分区：
文献类型：
--
作者：
Vivar, Raul;Humeres, Claudio;Diaz-Araya, Guillermo
心脏成纤维细胞向肌成纤维细胞的分化是心脏纤维化发展的关键过程，并且紧密依赖于转化生长因子β-1（TGF-β 1）。转录因子叉头盒O 1（FoxO 1）调节许多细胞功能，包括细胞凋亡，增殖和分化引起的细胞死亡。然而，这一过程的几个方面仍不清楚，包括FoxO 1在心脏成纤维细胞分化中的作用和TGF-β 1对FoxO 1的调节。在这里，我们报告说，TGF-β 1刺激FoxO 1的表达，促进其去磷酸化，核定位和转录活性在培养的心脏成纤维细胞。TGF-β 1还增加分化标志物，如α-平滑肌肌动蛋白、结缔组织生长因子和前胶原I，而它降低由胎牛血清引发的心脏成纤维细胞增殖。TGF-β 1还增加p21 waf/cip-周期抑制因子蛋白的水平，这是一种促进细胞周期停滞和心脏成纤维细胞分化的细胞生长抑制因子。此外，TGF-β 1增加心脏成纤维细胞收缩能力，如通过胶原凝胶收缩测定所评估的。TGF-β 1对心脏成纤维细胞分化的影响被FoxO 1下调所阻止，并被FoxO 1过表达所增强。因此，我们的研究结果表明，FoxO 1受TGF-β 1的调节，并在心脏成纤维细胞分化中发挥关键作用。我们认为FoxO 1是抗纤维化治疗的一个有吸引力的新靶点。(C)2015 Elsevier B. V.版权所有。
Cardiac fibroblast differentiation to myofibroblast is a crucial process in the development of cardiac fibrosis and is tightly dependent on transforming growth factor beta-1 (TGF-beta 1). The transcription factor forkhead box O1 (FoxO1) regulates many cell functions, including cell death by apoptosis, proliferation, and differentiation. However, several aspects of this process remain unclear, including the role of FoxO1 in cardiac fibroblast differentiation and the regulation of FoxO1 by TGF-beta 1. Here, we report that TGF-beta 1 stimulates FoxO1 expression, promoting its dephosphorylation, nuclear localization and transcriptional activity in cultured cardiac fibroblasts. TGF-beta 1 also increases differentiation markers such as a-smooth muscle actin, connective tissue growth factor, and pro-collagen I, whereas it decreases cardiac fibroblast proliferation triggered by fetal bovine serum. TGF-beta 1 also increases levels of p21waf/cip-cycle inhibiting factor protein, a cytostatic factor promoting cell cycle arrest and cardiac fibroblast differentiation. In addition, TGF-beta 1 increases cardiac fibroblast contractile capacity as assessed by collagen gel contraction assay. The effect of TGF-beta 1 on cardiac fibroblast differentiation was prevented by FoxO1 down-regulation and enhanced by FoxO1 overexpression. Thus, our findings reveal that FoxO1 is regulated by TGF-beta 1 and plays a critical role in cardiac fibroblast differentiation. We propose that FoxO1 is an attractive new target for anti-fibrotic therapy. (C) 2015 Elsevier B.V. All rights reserved.