The Akt/FoxO/p27Kip1 axis contributes to the anti-proliferation of pentoxifylline in hypertrophic scars
The Akt/FoxO/p27Kip1 axis contributes to the anti-proliferation of pentoxifylline in hypertrophic scars
复制标题
Akt/FoxO/p27(Kip1) 轴有助于抑制肥厚性疤痕中己酮可可碱的增殖
DOI：
10.1111/jcmm.14498
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发表时间：
2019-07-03
影响因子：
5.3
通讯作者：
Hu, Dahai
中科院分区：
文献类型：
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作者：
Yang, Fangfang;Chen, Erfei;Hu, Dahai
增生性瘢痕（HS）的特征是细胞外基质（ECM）蛋白的过度产生和沉积。黄嘌呤衍生的抗氧化剂戊茶碱（PTX）抑制HS的增殖、炎症和ECM积累。本研究旨在探讨PTX对HS的影响，进一步阐明PTX抗HS增殖的机制。我们发现，PTX可以显着减弱HS成纤维细胞的增殖和纤维化的动物HS模型。PTX对HSFs增殖的抑制作用呈剂量和时间依赖性，且主要通过细胞周期阻滞来实现。转录组测序显示PTX通过PI 3 K/Akt/FoxO 1信号通路激活p27（Kip 1）影响HS形成。PTX在蛋白水平下调TGF-β 1刺激的成纤维细胞中p-Akt的表达，上调p-FoxO 1的表达，同时激活p27（Kip 1）的表达。在HS小鼠模型中，PTX治疗导致胶原纤维有序化。结果显示，PTX调节TGF β 1诱导的成纤维细胞活化并抑制过度瘢痕形成。因此，PTX是治疗HS形成的有前途的药物。
Hypertrophic scars (HS) are characterized by the excessive production and deposition of extracellular matrix (ECM) proteins. Pentoxifylline (PTX), a xanthine derived antioxidant, inhibits the proliferation, inflammation and ECM accumulation of HS. In this study, we aimed to explore the effect of PTX on HS and further clarify the mechanism of PTX-induced anti-proliferation. We found that PTX could significantly attenuate proliferation of HS fibroblasts and fibrosis in an animal HS model. PTX inhibited the proliferation of HSFs in a dose- and time-dependent manner, and this growth inhibition was mainly mediated by cell cycle arrest. Transcriptome sequencing showed that PTX affects HS formation through the PI3K/Akt/FoxO1 signalling pathway to activate p27(Kip1). PTX down-regulated p-Akt and up-regulated p-FoxO1 in TGF-beta 1 stimulated fibroblasts at the protein level, and simultaneously, the expression of p27(Kip1) was activated. In a mouse model of HS, PTX treatment resulted in the ordering of collagen fibres. The results revealed that PTX regulates TGF beta 1-induced fibroblast activation and inhibits excessive scar formation. Therefore, PTX is a promising agent for the treatment of HS formation.