Terano T, Shiina T, Noguchi Y, Tanaka T, Tatsuno I, Saito Y, Yasuda T, Kitagawa M, Hirai A
Department of Internal Medicine, Chiba Municipal Hospital, Japan.
J Atheroscler Thromb. 1998;5(1):1-6. doi: 10.5551/jat1994.5.1.
Pravastatin, a HMG-CoA reductase inhibitor was found to inhibit DNA synthesis of vascular smooth muscle cells (VSMC) in a dose-dependent manner. Flow cytometric analysis demonstrated that pravastatin induced G1 arrest. Mevalonate restored the inhibitory effect of pravastatin on DNA synthesis and on cell cycle progression, suggesting the importance of mevalonate itself and/or its metabolites in VSMC proliferation. The major intermediate metabolites of mevalonate, geranylgeranyl-pyrophosphate (GGPP), farnesyl pyrophosphate (FPP) and IPP (isopentenyl pyrophosphate) were prepared in the form of liposomes, and the effects of GGPP, FPP and IPP on pravastatin induced inhibition of VSMC proliferation and G1 arrest were examined. Only GGPP restored the pravastatin-induced inhibition of DNA synthesis and G1 arrest. Pravastatin inhibited translocation of Rho small GTPase from cytosol to membrane. By the addition of GGPP, Rho small GTPase are geranylgeranylated and translocated to membranes during G1/S transition. These data suggest that GGPP, rather than FPP or IPP, is an essential metabolite among mevalonic acid metabolites for VSMC proliferation and the G1/S transition.
普伐他汀，一种HMG-CoA还原酶抑制剂，被发现以剂量依赖的方式抑制血管平滑肌细胞（VSMC）的DNA合成。流式细胞术分析表明普伐他汀诱导G1期阻滞。甲羟戊酸恢复了普伐他汀对DNA合成和细胞周期进程的抑制作用，表明甲羟戊酸本身和/或其代谢产物在VSMC增殖中具有重要作用。甲羟戊酸的主要中间代谢产物香叶基香叶基焦磷酸（GGPP）、法尼基焦磷酸（FPP）和异戊烯基焦磷酸（IPP）以脂质体的形式制备，并检测了GGPP、FPP和IPP对普伐他汀诱导的VSMC增殖抑制和G1期阻滞的影响。只有GGPP恢复了普伐他汀诱导的DNA合成抑制和G1期阻滞。普伐他汀抑制Rho小GTP酶从胞质溶胶向膜的转位。通过添加GGPP，Rho小GTP酶在G1/S期转变过程中被香叶基香叶基化并转位到膜上。这些数据表明，对于VSMC增殖和G1/S期转变，GGPP而非FPP或IPP是甲羟戊酸代谢产物中的必需代谢物。
