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探讨丹参酮 IIA 诱导活化的大鼠肝星状细胞凋亡的分子机制。

Explore the Molecular Mechanism of Apoptosis Induced by Tanshinone IIA on Activated Rat Hepatic Stellate Cells.

机构信息

School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan 333, Taiwan ; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan.

出版信息

Evid Based Complement Alternat Med. 2012;2012:734987. doi: 10.1155/2012/734987. Epub 2012 Dec 30.

Abstract

Since the activated hepatic stellate cell (HSC) is the predominant event in the progression of liver fibrosis, selective clearance of HSC should be a potential strategy in therapy. Salvia miltiorrhiza roots ethanol extract (SMEE) remarkably ameliorates liver fibrogenesis in DMN-administrated rat model. Next, tanshinone IIA (Tan IIA), the major compound of SMEE, significantly inhibited rat HSC viability and led to cell apoptosis. Proteome tools elucidated that increased prohibitin is involved in cell cycle arrest under Tan IIA is the treatment while knockdown of prohibitin could attenuate Tan IIA-induced apoptosis. In addition, Tan IIA mediated translocation of C-Raf which interacted with prohibitin activating MAPK and inhibiting AKT signaling in HSC. MAPK antagonist suppressed ERK phosphorylation which was necessary for Tan IIA-induced expression of Bax and cytochrome c. PD98059 also abolished Tan IIA-modulated cleavage of PARP. Our findings suggested that Tan IIA could contribute to apoptosis of HSC by promoting ERK-Bax-caspase pathways through C-Raf/prohibitin complex.

摘要

由于活化的肝星状细胞(HSC)是肝纤维化进展的主要事件,因此选择性清除 HSC 应该是治疗的潜在策略。丹参根乙醇提取物(SMEE)显著改善 DMN 给药大鼠模型中的肝纤维化发生。接下来,丹参酮 IIA(Tan IIA),SMEE 的主要成分,显著抑制大鼠 HSC 的活力并导致细胞凋亡。蛋白质组学工具阐明,在 Tan IIA 处理下,细胞周期停滞涉及到抑制素的增加,而抑制素的敲低可以减弱 Tan IIA 诱导的细胞凋亡。此外,Tan IIA 介导 C-Raf 的易位,C-Raf 与抑制素相互作用,在 HSC 中激活 MAPK 并抑制 AKT 信号通路。MAPK 拮抗剂抑制 ERK 磷酸化,这对于 Tan IIA 诱导 Bax 和细胞色素 c 的表达是必需的。PD98059 还消除了 Tan IIA 调节的 PARP 切割。我们的研究结果表明,Tan IIA 通过促进 ERK-Bax-胱天蛋白酶途径,通过 C-Raf/抑制素复合物,促进 HSC 的凋亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2973/3546466/fb8e2ff8e946/ECAM2012-734987.001.jpg

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