Rho依赖性对HMG CoA还原酶抑制剂（他汀类药物）诱导结缔组织生长因子（CTGF）的抑制作用。
Rho-dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins).
作者信息
Eberlein M, Heusinger-Ribeiro J, Goppelt-Struebe M
机构信息
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Loschgestrasse 8, D-91054 Erlangen, Germany.
出版信息
Br J Pharmacol. 2001 Aug;133(7):1172-80. doi: 10.1038/sj.bjp.0704173.
It was supposed that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase (statins) might inhibit the expression of the fibrosis-related factor CTGF (connective tissue growth factor) by interfering with the isoprenylation of Rho proteins. The human renal fibroblast cell line TK173 was used as an in vitro model system to study the statin-mediated modulation of the structure of the actin cytoskeleton and of the expression of CTGF mRNA. Incubation of the cells with simvastatin or lovastatin time-dependently and reversibly changed cell morphology and the actin cytoskeleton with maximal effects observed after about 18 h. Within the same time period, statins reduced the basal expression of CTGF and interfered with CTGF induction by lysophosphatidic acid (LPA) or transforming growth factor beta. Simvastatin and lovastatin proved to be much more potent than pravastatin (IC(50) 1 - 3 microM compared to 500 microM). The inhibition of CTGF expression was prevented when the cells were incubated with mevalonate or geranylgeranylpyrophosphate (GGPP) but not by farnesylpyrophosphate (FPP). Specific inhibition of geranylgeranyltransferase-I by GTI-286 inhibited LPA-mediated CTGF expression whereas an inhibitor of farnesyltransferases FTI-276 was ineffective. Simvastatin reduced the binding of the small GTPase RhoA to cellular membranes. The effect was prevented by mevalonate and GGPP, but not FPP. These data are in agreement with the hypothesis that interference of statins with the expression of CTGF mRNA is primarily due to interference with the isoprenylation of RhoA, in line with previous studies, which have shown that RhoA is an essential mediator of CTGF induction. The direct interference of statins with the synthesis of CTGF, a protein functionally related to the development of fibrosis, may thus be a novel mechanism underlying the beneficial effects of statins observed in renal diseases.
据推测，3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶抑制剂（他汀类药物）可能通过干扰Rho蛋白的异戊二烯化来抑制纤维化相关因子CTGF（结缔组织生长因子）的表达。人肾成纤维细胞系TK173被用作体外模型系统，以研究他汀类药物介导的肌动蛋白细胞骨架结构调节和CTGF mRNA表达。用辛伐他汀或洛伐他汀孵育细胞，可使细胞形态和肌动蛋白细胞骨架随时间依赖性且可逆地发生变化，约18小时后观察到最大效应。在同一时间段内，他汀类药物降低了CTGF的基础表达，并干扰了溶血磷脂酸（LPA）或转化生长因子β对CTGF的诱导作用。辛伐他汀和洛伐他汀被证明比普伐他汀更有效（IC(50)为1 - 3 microM，而普伐他汀为500 microM）。当细胞与甲羟戊酸或香叶基香叶基焦磷酸（GGPP）孵育时，CTGF表达的抑制作用被阻止，但法尼基焦磷酸（FPP）则无此作用。GTI-286对香叶基香叶基转移酶-I的特异性抑制作用抑制了LPA介导的CTGF表达，而法尼基转移酶抑制剂FTI-276则无效。辛伐他汀降低了小GTP酶RhoA与细胞膜的结合。甲羟戊酸和GGPP可阻止该效应，但FPP则不能。这些数据与以下假设一致，即他汀类药物对CTGF mRNA表达的干扰主要是由于对RhoA异戊二烯化的干扰，这与先前的研究一致，先前的研究表明RhoA是CTGF诱导的重要介质。因此，他汀类药物对CTGF合成的直接干扰，CTGF是一种与纤维化发展功能相关的蛋白质，可能是他汀类药物在肾脏疾病中观察到的有益作用的新机制。
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