Rho-dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins).
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.
Eberlein
M
M
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Loschgestrasse 8, D-91054 Erlangen, Germany.
Heusinger-Ribeiro
J
J
Goppelt-Struebe
M
M
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D015152:Blotting, Northern; D002460:Cell Line; D055513:Connective Tissue Growth Factor; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008148:Lovastatin / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes; D019821:Simvastatin / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology
D000199:Actins; C526317:CCN2 protein, human; D006133:Growth Substances; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D012717:Sesquiterpenes; D055513:Connective Tissue Growth Factor; C004808:farnesyl pyrophosphate; D008148:Lovastatin; D019821:Simvastatin; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D017035:Pravastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid