Nègre-Aminou P, van Vliet A K, van Erck M, van Thiel G C, van Leeuwen R E, Cohen L H
TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands.
Biochim Biophys Acta. 1997 Apr 21;1345(3):259-68. doi: 10.1016/s0005-2760(96)00184-1.
The effects of 6 HMG-CoA reductase inhibitors: pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin were analyzed in cultured human smooth muscle cells, fibroblasts, endothelial cells and myoblasts. In vascular smooth muscle cells, pravastatin was a much weaker inhibitor of cholesterol synthesis than the 5 other drugs which displayed equally strong inhibitory potency. The anti-proliferative effects of these 6 drugs were analyzed by measuring cell number and mitochondrial dehydrogenase activity (MTT assay) after 3 days of incubation. IC25 values for inhibition of proliferation were very similar among the 4 cell types and were in the following order of magnitude: pravastatin << lovastatin = simvastatin = atorvastatin = fluvastatin << cerivastatin. Only in the case of pravastatin was proliferation inhibited at lower concentration in smooth muscle cells than in the other cell types. Proliferation was also assessed by measuring DNA synthesis in these cells. A 3 day-incubation with 1 microM of pravastatin had no effect on this parameter in all 4 cell types. However, 1 microM of simvastatin or lovastatin caused either an inhibition (in smooth muscle cells and endothelial cells) or stimulation (in fibroblasts) of this process. The effects of simvastatin on cell number, mitochondrial dehydrogenase activity and DNA synthesis were counteracted by simultaneous mevalonate addition. Simvastatin treatment was also associated with a change in the post-translational modification of the ras protein in smooth muscle cells, probably by inhibition of its farnesylation. Moreover, simvastatin treatment blocked the PDGF and bFGF-induced DNA synthesis in synchronized smooth muscle cells, whereas it does not affect the fetal calf serum-induced DNA synthesis in synchronized fibroblasts, suggesting that simvastatin blocks various steps of the cell cycle and that this effect depends on the cell type and the growth signalling pathway activated.
分析了6种HMG-CoA还原酶抑制剂：普伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、氟伐他汀和西立伐他汀对培养的人平滑肌细胞、成纤维细胞、内皮细胞和成肌细胞的作用。在血管平滑肌细胞中，普伐他汀对胆固醇合成的抑制作用比其他5种显示出同等强效抑制作用的药物弱得多。通过在孵育3天后测量细胞数量和线粒体脱氢酶活性（MTT法）来分析这6种药物的抗增殖作用。4种细胞类型中抑制增殖的IC25值非常相似，其大小顺序如下：普伐他汀<<洛伐他汀 = 辛伐他汀 = 阿托伐他汀 = 氟伐他汀<<西立伐他汀。仅在普伐他汀的情况下，平滑肌细胞中增殖在较低浓度下受到抑制，而在其他细胞类型中则不然。还通过测量这些细胞中的DNA合成来评估增殖情况。用1微摩尔普伐他汀孵育3天对所有4种细胞类型的该参数均无影响。然而，1微摩尔辛伐他汀或洛伐他汀对该过程要么产生抑制作用（在平滑肌细胞和内皮细胞中），要么产生刺激作用（在成纤维细胞中）。同时添加甲羟戊酸可抵消辛伐他汀对细胞数量、线粒体脱氢酶活性和DNA合成的影响。辛伐他汀治疗还与平滑肌细胞中ras蛋白翻译后修饰的变化有关，可能是通过抑制其法尼基化。此外，辛伐他汀治疗可阻断血小板衍生生长因子（PDGF）和碱性成纤维细胞生长因子（bFGF）诱导的同步化平滑肌细胞中的DNA合成，而不影响胎牛血清诱导的同步化成纤维细胞中的DNA合成，这表明辛伐他汀可阻断细胞周期的各个步骤，且这种作用取决于细胞类型和激活的生长信号通路。
