High concentration simvastatin induces apoptosis in fibroblast-like synoviocytes from patients with rheumatoid arthritis.
High concentration simvastatin induces apoptosis in fibroblast-like synoviocytes from patients with rheumatoid arthritis.
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发表时间：
2008-02
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通讯作者：
K. Yokota;F. Miyoshi;T. Miyazaki;Kojiro Sato;Yoshihiro Yoshida;Y. Asanuma;Y. Akiyama;T. Mimura
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作者：
K. Yokota;F. Miyoshi;T. Miyazaki;Kojiro Sato;Yoshihiro Yoshida;Y. Asanuma;Y. Akiyama;T. Mimura
目的我们以前报道过，10 mg/天的辛伐他汀可显著降低活动性类风湿关节炎（RA）伴高胆固醇血症患者的临床评分。我们还报道了辛伐他汀的一定药理学浓度，即，0.05 - 0.1 μ M，在体外抑制RA患者来源的成纤维细胞样滑膜细胞（FLS）中白细胞介素6（IL-6）和IL-8的产生以及肿瘤坏死因子-α（TNF-α）诱导的细胞增殖。我们从细胞活力和细胞凋亡的角度研究了辛伐他汀对FLS的其他影响。方法RA FLS培养48 h后加入或不加入0.05 - 50 μ M辛伐他汀。使用3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四唑（MTT）测定法测定细胞活力。细胞凋亡测定流式细胞仪分析使用碘化丙啶和annexin-V。半胱天冬酶-3和-9活性进行了分析，比色法。结果高浓度辛伐他汀，即，1.0 - 50 μ M，以剂量依赖性方式降低FLS中的细胞活力并诱导显著的凋亡。辛伐他汀诱导的细胞凋亡依赖于caspase-3和caspase-9。这些影响被完全逆转的存在下，甲羟戊酸或geranylgeranyl-pyrophosphate，但不存在的法呢基-焦磷酸。此外，香叶基香叶基转移酶抑制剂和RhoA激酶抑制剂模拟辛伐他汀的作用。结论低浓度辛伐他汀（药理范围）和高浓度辛伐他汀对FLS的影响不同：（1）低浓度辛伐他汀抑制TNF-α诱导的FLS产生IL-6、IL-8和细胞增殖;（2）高浓度辛伐他汀诱导FLS凋亡。了解辛伐他汀的剂量依赖性双相效应可能对其在RA治疗中的临床应用具有重要意义。
OBJECTIVE We previously reported that 10 mg/day of simvastatin significantly reduced clinical scores of rheumatoid arthritis (RA) in patients with active RA with hypercholesterolemia. We have also reported that a certain pharmacological concentration of simvastatin, i.e., 0.05-0.1 microM, inhibits the production of interleukin 6 (IL-6) and IL-8 and the cell proliferation induced by tumor necrosis factor-alpha (TNF-alpha) in fibroblast-like synoviocytes (FLS) derived from patients with RA in vitro. We investigated other effects of simvastatin on FLS from the standpoint of cell viability and apoptosis. METHODS RA FLS were cultured with or without 0.05-50 microM simvastatin for 48 h. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was measured by flow cytometric analysis using propidium iodide and annexin-V. Caspase-3 and -9 activities were analyzed by colorimetric assays. RESULTS High concentrations of simvastatin, i.e., 1.0-50 microM, reduced cell viability and induced prominent apoptosis in FLS in a dose-dependent manner. The apoptosis induced by simvastatin was caspase-3- and caspase-9-dependent. These effects were completely reversed in the presence of mevalonic acid or geranylgeranyl-pyrophosphate, but not in the presence of farnesyl-pyrophosphate. Further, a geranylgeranyl transferase inhibitor and a RhoA kinase inhibitor mimicked the effect of simvastatin. CONCLUSION These data, together with our previous report, suggest that low (pharmacological range) and high concentrations of simvastatin affect FLS differently: (1) at a low concentration, it inhibits IL-6 and IL-8 production and the cell proliferation of FLS induced by TNF-alpha (2) at high concentrations, it induces apoptosis in FLS. Understanding this dose-dependent biphasic effect of simvastatin may prove important for its clinical applications in the treatment of RA.