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首页> 外文期刊>Laboratory investigation >Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats
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Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

机译：阿托伐他汀抑制增殖和凋亡，但诱导肝成纤维细胞衰老，从而减轻大鼠肝纤维化

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Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile duct-ligated (BDL) rats in vivo. Here, we have further investigated the underlying mechanisms. Primary rat hepatic stellate cells (HSC) were isolated and culture-activated to hepatic MFB. Following 3 days of incubation with atorvastatin (10?4, 10?5 and 10?6?M), transcription levels of profibrotic cytokines (transforming growth factor-β1, connective tissue growth factor and TIMP1) and procollagen Ia were analyzed by real time PCR. Proliferation was investigated by 5'-bromo-2'-deoxyuridine assays. α-Smooth muscle actin protein expression was examined by western blotting. Fluorescence-activated cell sorting analysis of Annexin V and propidium iodide were used to measure apoptosis. Furthermore, p21 western blotting and β-galactosidase staining were investigated in MFB as senescence markers. Subsequently, hepatic expression of desmin and senescence markers were analyzed in the livers of rats receiving atorvastatin (15?mg/kg*d) for 1 week starting 3 and 5 weeks after BDL. Atorvastatin inhibited the activation of HSC to MFB and decreased cytokine and collagen production in MFB in vitro. In addition, proliferation, cytokine and collagen production of MFB were reduced by atorvastatin. Atorvastatin initiated apoptosis at 10?4?M and attenuated it at 10?5?M. Atorvastatin induced p21 protein expression and β-galactosidase staining of MFB in vitro and in vivo. Atorvastatin elicits similiar effects on MFB as previously seen in vivo: it decreases MFB turnover and fibrogenesis. We suggest that a further mechanism explaining these effects is senescence of cells.
机译：肝成肌纤维细胞（MFB）显示出增加的增殖，迁移和胶原蛋白生成，这对于肝纤维化至关重要。阿托伐他汀治疗可抑制体内胆管结扎（BDL）大鼠的MFB增殖，凋亡和细胞因子的产生。在这里，我们进一步研究了潜在的机制。分离大鼠原代肝星状细胞（HSC）并培养激活至肝MFB。在与阿托伐他汀（10？4、10？5和10？6？M）孵育3天后，实时分析了纤维化细胞因子（转化生长因子-β1，结缔组织生长因子和TIMP1）和胶原蛋白Ia的转录水平PCR。通过5'-溴-2'-脱氧尿苷测定研究增殖。通过蛋白质印迹检查了α-平滑肌肌动蛋白的表达。膜联蛋白V和碘化丙啶的荧光激活细胞分选分析用于测量细胞凋亡。此外，在MFB中研究了p21蛋白质印迹和β-半乳糖苷酶染色作为衰老标记。随后，在BDL后3周和5周开始，在接受阿托伐他汀（15？mg / kg * d）1周的大鼠的肝脏中分析结蛋白的肝表达和衰老标记。阿托伐他汀在体外抑制HSC向MFB的活化并降低MFB中的细胞因子和胶原蛋白的产生。此外，阿托伐他汀可降低MFB的增殖，细胞因子和胶原蛋白的产生。阿托伐他汀在10？4？M开始凋亡，在10？5？M减弱。阿托伐他汀在体外和体内诱导MFB的p21蛋白表达和β-半乳糖苷酶染色。如先前在体内所见，阿托伐他汀对MFB产生相似的作用：它降低了MFB转换和纤维生成。我们建议解释这些影响的另一机制是细胞衰老。

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