All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells
All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells
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DOI：
10.1016/s0021-9150(03)00301-0
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发表时间：
2003-10-01
期刊：
影响因子：
5.3
通讯作者：
Ichihara, K
中科院分区：
文献类型：
--
作者：
Kaneta, S;Satoh, K;Ichihara, K
3-羟基-3-甲基-戊二酰-CoA（HMG-CoA）还原酶抑制剂（他汀类药物）在高胆固醇血症患者中有效降低心血管疾病风险，这不仅是因为其降低胆固醇的作用，还因为其多效性作用，如改善内皮细胞功能障碍。另一方面，他汀类药物防止各种细胞的细胞增殖，包括内皮细胞。我们研究了目前所有他汀类药物对培养的大鼠肺静脉内皮细胞活力的影响。洛伐他汀，辛伐他汀，阿托伐他汀，氟伐他汀和西立伐他汀，这是疏水性他汀类药物，显着降低与DNA片段化，DNA梯状和半胱天冬酶-3的激活相关的细胞活力，表明凋亡细胞死亡。普伐他汀是一种亲水性他汀类药物，但不诱导细胞凋亡。疏水性他汀类药物诱导的内皮细胞凋亡与凋亡相关的细胞内信号转导系统的激活、RhoA在膜上的定位减弱、Rac I的诱导、c-Jun N-末端激酶和c-Jun磷酸化的增加有关。(C)2003年由Elsevier爱尔兰有限公司出版
3-Hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) are effective in patients with hypercholesterolemia to reduce risk of cardiovascular diseases, because of not only their lowering cholesterol effects but also their pleiotropic effects, such as improvement of endothelial cell dysfunction. On the other hand, statins prevent cell proliferation of various cells, including endothelial cells. We examined effects of all statins available at present on the viability of cultured rat pulmonary vein endothelial cells. Lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin, which are hydrophobic statins, markedly reduced cell viability associated with DNA fragmentation, DNA laddering and activation of caspase-3, suggesting apoptotic cell death. Pravastatin, which is a hydrophilic statin, however, did not induce cell apoptosis. Apoptosis induced by hydrophobic statins was associated with activation of apoptosis-related intracellular signal transduction systems; attenuation of localization of RhoA to the membrane, induction of Rac I, and increase in phosphorylation of c-Jun N-terminal kinase and c-Jun. Endothelial cell apoptosis is underlying the improvement of the endothelial dysfunction with hydrophobic statins. (C) 2003 Published by Elsevier Ireland Ltd.