Statins have biphasic effects on angiogenesis
Statins have biphasic effects on angiogenesis
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DOI：
10.1161/hc0602.103393
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发表时间：
2002-02-12
期刊：
影响因子：
37.8
通讯作者：
Cooke, JP
中科院分区：
文献类型：
--
作者：
Weis, M;Heeschen, C;Cooke, JP
背景-他汀类药物抑制HMG-CoA还原酶以减少调节多种细胞功能的胆固醇和类异戊二烯的合成。我们研究了他汀类药物西立伐他汀和阿托伐他汀对血管生成的影响，在体外和vivo.Methods和结果，内皮细胞增殖，迁移和分化增强低浓度（0.005至0.01 μ mol/L），但显着抑制在高他汀浓度（0.05至1 μ mol/L）。高浓度的抗血管生成作用与血管内皮生长因子的内皮释放减少和内皮细胞凋亡增加有关，并被香叶基香叶基焦磷酸逆转。在小鼠模型中，低剂量他汀类药物治疗（0.5 mg . kg（-1）。d（-1）），但高浓度西立伐他汀或阿托伐他汀（2.5 mg . kg（-1）。d（-1））。尽管高剂量他汀类药物治疗能有效降低高脂血症载脂蛋白E缺陷小鼠的血脂水平，但它损害而不是增强了血管生成。最后，高剂量的西立伐他汀降低肿瘤生长和肿瘤血管形成在小鼠刘易斯肺癌model.Conclusions-HMG-CoA还原酶抑制具有双相剂量依赖性的影响血管生成是脂质独立的，并与内皮细胞凋亡和血管内皮生长因子信号的改变。他汀类药物在低治疗浓度下具有促血管生成作用，但在高浓度下具有血管抑制作用，其可被香叶基香叶基焦磷酸逆转。在临床相关剂量下，他汀类药物可通过对香叶基化蛋白的作用调节人体血管生成。
Background-Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo.Methods and Results-Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 mumol/L) but significantly inhibited at high statin concentrations (0.05 to 1 mumol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg . kg(-1) . d(-1)) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg . kg(-1) . d(-1)). Despite the fact that high-dose statin treatment was effective at reducing lipid levels in hyperlipidemic apolipoprotein E-deficient mice, it impaired rather than enhanced angiogenesis. Finally, high-dose cerivastatin decreased tumor growth and tumor vascularization in a murine Lewis lung cancer model.Conclusions-HMG-CoA reductase inhibition has a biphasic dose-dependent effect on angiogenesis that is lipid independent and associated with alterations in endothelial apoptosis and vascular endothelial growth factor signaling. Statins have proangiogenic effects at low therapeutic concentrations but angiostatic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate. At clinically relevant doses, statins may modulate angiogenesis in humans via effects on geranylated proteins.