Statins inhibited erythropoietin-induced proliferation of rat vascular smooth muscle cells.
Statins inhibited erythropoietin-induced proliferation of rat vascular smooth muscle cells.
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DOI：
10.1016/j.ejphar.2010.08.053
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发表时间：
2010-12
影响因子：
5
通讯作者：
Tae Kaneda;S. Tsuruoka;A. Fujimura
中科院分区：
文献类型：
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作者：
Tae Kaneda;S. Tsuruoka;A. Fujimura
促红细胞生成素（EPO）直接刺激血管平滑肌细胞增殖，这被认为是血液透析患者血管通路失败的机制之一。然而，EPO诱导血管平滑肌细胞增殖的确切机制尚不确定。HMG-CoA还原酶抑制剂（他汀类药物）主要用于降低胆固醇水平，但也发挥其他作用，包括肾脏保护作用。本实验观察了不同浓度的他汀类药物对体外原代培养的大鼠血管平滑肌细胞（VSMCs）增殖的影响。通过[3 H]胸苷掺入法评估，EPO显著且浓度依赖性地增加DNA合成，通过WST-1测定评估细胞增殖，并激活p44/42 MAPK途径。治疗剂量的他汀类药物（普伐他汀，辛伐他汀，阿托伐他汀和氟伐他汀）在高胆固醇血症患者几乎完全抑制了所有的EPO诱导的影响，在浓度依赖性的方式。同时加入甲羟戊酸几乎完全逆转了他汀类药物的作用。单独的他汀类药物不影响细胞的基础增殖能力。他汀类药物的作用几乎相似。我们的结论是，他汀类药物抑制EPO诱导的大鼠VSMCs增殖至少部分通过抑制HMG-CoA还原酶活性。将来，他汀类药物可能被证明可用于治疗EPO诱导的血管通路增生。由于他汀类药物均显示出相当的效应，无论其毒性如何，这些效应可能是类效应。
Erythropoietin (EPO) directly stimulates the proliferation of vascular smooth muscle cells, and this is believed to be one of the mechanisms of vascular access failure of hemodialysis patients. However, precise mechanisms of the EPO-induced proliferation of vascular smooth muscle cells are not certain. HMG-CoA reductase inhibitors (statins) are primarily used to reduce cholesterol levels, but also exert other effects, including reno-protective effects. We evaluated the effect of several statins with various hydrophilicities on the EPO-induced proliferation of primary cultured rat vascular smooth muscle cells (VSMCs) in vitro. EPO significantly and concentration-dependently increased DNA synthesis as assessed by [3H]thymidine incorporation, cell proliferation as assessed by WST-1 assay, and activation of the p44/42MAPK pathway. Therapeutic doses of statins (pravastatin, simvastatin, atorvastatin and fluvastatin) in patients with hypercholesterolemia almost completely suppressed all of the EPO-induced effects in a concentration-dependent manner. Co-addition of mevalonic acid almost completely reversed the effects of statins. Statin alone did not affect the basal proliferation capacity of the cells. The effects were almost similar among the statins. We concluded that statins inhibited EPO-induced proliferation in rat VSMCs at least partly through their inhibition of HMG-CoA reductase activity. In the future, statins might prove useful for the treatment of EPO-induced hyperplasia of vascular access. Because the statins all showed comparable effects irrespective of their hydrophilicities, these effects might be a class effect.