Journal article
Rho-dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins)
British journal of pharmacology, Vol.133(7), pp.1172-1180
08/2001
DOI: 10.1038/sj.bjp.0704173
PMCID: PMC1572879
PMID: 11487529
Abstract
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 μ
M
compared to 500 μ
M
).
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.
Details
- Title: Subtitle
- Rho-dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins)
- Creators
- Michael Eberlein - Medizinische Klinik IV, Universität Erlangen-Nürnberg, Loschgestrasse 8, D-91054 Erlangen, GermanyJuliane Heusinger-Ribeiro - Medizinische Klinik IV, Universität Erlangen-Nürnberg, Loschgestrasse 8, D-91054 Erlangen, GermanyMargarete Goppelt-Struebe - Medizinische Klinik IV, Universität Erlangen-Nürnberg, Loschgestrasse 8, D-91054 Erlangen, Germany
- Resource Type
- Journal article
- Publication Details
- British journal of pharmacology, Vol.133(7), pp.1172-1180
- DOI
- 10.1038/sj.bjp.0704173
- PMID
- 11487529
- PMCID
- PMC1572879
- ISSN
- 0007-1188
- eISSN
- 1476-5381
- Language
- English
- Date published
- 08/2001
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
- Record Identifier
- 9984094580302771
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