The antioxidant (-)-epigallocatechin-3-gallate inhibits rat hepatic stellate cell proliferation in vitro by blocking the tyrosine phosphorylation and reducing the gene expression of platelet-derived growth factor-β receptor
The antioxidant (-)-epigallocatechin-3-gallate inhibits rat hepatic stellate cell proliferation in vitro by blocking the tyrosine phosphorylation and reducing the gene expression of platelet-derived growth factor-β receptor
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DOI：
10.1074/jbc.m212042200
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发表时间：
2003-06-27
影响因子：
4.8
通讯作者：
Zhang, L
中科院分区：
文献类型：
--
作者：
Chen, AP;Zhang, L
在肝纤维发生过程中，静止的肝星状细胞（HSC）变得活跃并转分化为肌成纤维细胞样细胞。这一过程与细胞增殖的增加、储存的维生素 A 液滴的损失以及细胞外基质成分的过度产生和沉积同时发生。 HSC 激活与细胞因子受体的连续表达相关，包括血小板源性生长因子-β 受体 (PDGF-betaR)。尽管其潜在机制尚不完全清楚，但人们普遍认为氧化应激在肝纤维化过程中 HSC 的激活中发挥着关键作用。我们最近证明，绿茶提取物中的主要成分抗氧化剂 (-)-表没食子儿茶素没食子酸酯 (EGCG) 可显着抑制传代 HSC 的增殖。本研究的目的是阐明潜在机制。由于PDGF是HSC的有效丝裂原并介导早期增殖反应，因此推测EGCG可能通过干扰PDGF信号转导来抑制HSC增殖。在本报告中，我们证明了 EGCG 分两步显着且有效地抑制了原代和传代 HSC 的增殖。该多酚化合物通过快速阻断血清中 PDGF 引发的 PDGF-betaR 中酪氨酸的磷酸化来启动其抑制作用。这个动作持续时间很短，持续了几个小时。此外，这种抗氧化剂通过阻断基因转录所需的转录因子激活蛋白-1 和 NF-κB 的激活来抑制 PDGF-betaR 的基因表达。后者的作用持续有效不少于48小时。这些结果为 EGCG 抑制 HSC 生长的机制提供了新的见解。天然抗氧化剂的抑制作用、其长期饮用饮料且不会对健康产生不良影响以及较高的抗氧化能力，使其成为治疗和预防肝纤维化的良好候选者。
During hepatic fibrogenesis, quiescent hepatic stellate cells (HSC) become active and trans-differentiate into myofibroblast-like cells. This process coincides with an increase in cell proliferation, loss of stored vitamin A droplets, and excessive production and deposition of extracellular matrix components. HSC activation is coupled with the sequential expression of cytokine receptors, including platelet-derived growth factor-beta receptor (PDGF-betaR). Although the underlying mechanisms remain incompletely understood, it is widely accepted that oxidative stress plays critical roles in activation of HSC during hepatic fibrogenesis. We have recently demonstrated that the antioxidant (-)-epigallocatechin gallate (EGCG), a major component in green tea extracts, significantly inhibited the proliferation of passaged HSC. The aim of the present study is to elucidate the underlying mechanisms. Since PDGF is a potent mitogen for HSC and mediates the early proliferative response, it was hypothesized that EGCG might inhibit HSC proliferation by interfering with the PDGF signal transduction. In this report, we demonstrated that EGCG, in two steps, significantly and effectively inhibited the proliferation of primary and passaged HSC. The polyphenolic compound initiated its inhibitory action by rapidly blocking the phosphorylation of tyrosines in PDGF-betaR elicited by PDGF in serum. This action was short lived, persisting for a few hours. In addition, this antioxidant inhibited the gene expression of PDGF-betaR by blocking the activation of transcription factors activator protein-1 and NF-kappaB, which were required for the gene transcription. The latter action remained effective for no less than 48 hours. These results provided a novel insight into the mechanisms by which EGCG inhibits HSC growth. The inhibitory effect of the natural antioxidant, its long history of beverage consumption without adverse health effects, and higher potent antioxidant capability make it a good candidate for therapeutic treatment and prevention of hepatic fibrosis.