Atorvastatin induces apoptosis by a caspase-9-dependent pathway: an in vitro study on activated rat hepatic stellate cells.
Atorvastatin induces apoptosis by a caspase-9-dependent pathway: an in vitro study on activated rat hepatic stellate cells.
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阿托伐他汀通过caspase-9依赖性途径诱导凋亡：对活化大鼠肝星状细胞的体外研究。
DOI：
10.1111/j.1478-3231.2008.01682.x
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发表时间：
2008-04
影响因子：
6.7
通讯作者：
Saile, Bernhard
中科院分区：
文献类型：
--
作者：
Aprigliano, Isabella;Dudas, Joszef;Ramadori, Giuliano;Saile, Bernhard
他汀类药物显示具有胆固醇非依赖性特性，如抗炎和免疫调节。活化的肝星状细胞（HSC）在受损的肝脏中获得合成基质蛋白的能力。我们检验了阿托伐他汀可能能够诱导HSC凋亡的假设。将大鼠HSC的原代培养物暴露于阿托伐他汀、甲羟戊酸和U 0126。通过流式细胞术和激光扫描显微镜对活的、凋亡的和坏死的HSC进行定量。通过流式细胞术进行细胞周期分析。通过Western blot和电泳迁移率变动分析研究促凋亡和抗凋亡因子。使用比色试剂盒计算半胱天冬酶的蛋白酶活性。阿托伐他汀导致G2期阻滞并诱导活化的HSC凋亡。阿托伐他汀介导的细胞凋亡可被甲羟戊酸和U 0126联合给药阻断。阿托伐他汀对CD 95、CD 95 L、NF-κB、p53和p21 WAF 1基因表达无影响。阿托伐他汀诱导的活化HSC细胞凋亡与caspase-9和-3蛋白酶活性增加有关。bcl-系统的主要蛋白质的基因表达表明，截短的Bid参与阿托伐他汀介导的细胞凋亡。通过加入U 0126阻断细胞外信号调节蛋白激酶（ERK 1/2）的激活，我们可以阻止阿托伐他汀诱导的细胞凋亡。通过Western blot，我们不能检测到c-jun N-末端激酶（JNK）的活化的任何变化。阿托伐他汀通过ERK依赖性的Bid裂解和高度增加的caspase-9和-3蛋白酶活性诱导活化HSC的凋亡。JNK不参与阿托伐他汀介导的HSC凋亡。
Statins are shown to have cholesterol-independent properties such as anti-inflammation and immunomodulation. Activated hepatic stellate cells (HSCs) acquire the capacity to synthesize matrix proteins in damaged liver. We tested the hypothesis that atorvastatin may be capable of inducing apoptosis in HSCs. Primary cultures of rat HSCs were exposed to atorvastatin, mevalonic acid and U0126. Quantification of living, apoptotic and necrotic HSCs was performed by flow cytometry and laser-scan microscopy. Cell-cycle analysis was performed by flow cytometry. Pro- and anti-apoptotic factors were investigated by Western blot and electrophoresis mobility shift assay. Protease activity of caspases was calculated using a colorimetric kit. Atorvastatin leads to a G2-arrest and induces apoptosis in activated HSCs. Atorvastatin-mediated apoptosis could be blocked by co-administration of mevalonic acid and U0126. No effects of atorvastatin on gene expression of CD95, CD95L, NF-κB, p53 and p21WAF1 could be observed. Atorvastatin-induced apoptosis in activated HSCs is related to an increased protease activity of caspase-9 and -3. Gene expression of the major proteins of the bcl-system shows that truncated Bid is involved in apoptosis mediated by atorvastatin. By blocking the extracellular signal-regulated protein kinase (ERK1/2) activation by adding U0126, we could prevent the apoptosis induced by atorvastatin. By Western blot we could not detect any change in the activation of c-jun N-terminal kinase (JNK). Atorvastatin induces apoptosis in activated HSCs acting through an ERK-dependent cleavage of Bid and a highly increased protease activity of caspase-9 and -3. JNK is not involved in atorvastatin-mediated apoptosis in HSCs.
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影响因子：
2.9
作者：
Cilla, DD;Gibson, DM;Sedman, AJ
通讯作者：
Sedman, AJ
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Ramadori, G
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作者：
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7.4
作者：
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