Rho‐dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins)

Eberlein, Michael; Heusinger‐Ribeiro, Juliane; Goppelt‐Struebe, Margarete

doi:10.1038/sj.bjp.0704173

Cited by 124 publications

(97 citation statements)

References 50 publications

(63 reference statements)

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“…In some experiments, the aforementioned chemicals were applied in the presence of mevalonate (100 and 500 M), cholesterol (100 M; both are from Sigma; these concentrations were chosen according to the literature (34,35)), or of inhibitors of the mitogen-activated protein kinase (MAPK) kinase (MEK), PD98059 (25 M), or the p38 mitogen-activated protein kinase (MAPK) kinase, SB233580 (20 M; both were purchased from Calbiochem). For assessment of overall cell proliferation, 5-bromo-2Ј-deoxyuridine (BrdUrd) (10 M; Sigma) was added to culture medium 24 h before the slices were fixed.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Baudry

Liu

et al. 2004

Journal of Biological Chemistry

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Inflammatory responses involving microglia, the resident macrophages of the brain, are thought to contribute importantly to the progression of Alzheimer's disease (AD) and possibly other neurodegenerative disorders. The present study tested whether the mevalonate-isoprenoid biosynthesis pathway, which affects inflammation in many types of tissues, tonically regulates microglial activation. This question takes on added significance given the potential use of statins, drugs that block the rate-limiting step (3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase)) in mevalonate and cholesterol synthesis, in AD treatment. Both mevastatin and simvastatin caused a concentration-and time-dependent activation of microglia in cultured rat hippocampal slices. This response consisted of a transformation of the cells from a typical resting configuration to an amoeboid, macrophage-like morphology, increased expression of a macrophage antigen, and up-regulation of the cytokine tumor necrosis factor-␣. Evidence for proliferation was also obtained. Statin-induced microglial changes were blocked by mevalonate but not by cholesterol, indicating that they were probably due to suppression of isoprenoid synthesis. In accord with this, the statin effects were absent in slices co-incubated with geranylgeranyl pyrophosphate, a mevalonate product that provides for the prenylation of Rho GTPases. Finally, PD98089, a compound that blocks activation of extracellularly regulated kinases1/2, suppressed statin-induced up-regulation of tumor necrosis factor-␣ but had little effect on microglial transformation. These results suggest that 1) the mevalonate-isoprenoid pathway is involved in regulating microglial morphology and in controlling expression of certain cytokines and 2) statins have the potential for enhancing a component of AD with uncertain relationships to other features of the disease.High levels of cholesterol, and in particular of cholesterol esters (1), influence the generation and aggregation of ␤-amyloid peptides in dissociated cell cultures (2-6) and transgenic mice (7). Patients with high plasma cholesterol levels and cardiovascular diseases have increased risk of Alzheimer's disease (AD) 1 (8 -10), and there is evidence that statins, a family of compounds that inhibit the rate-limiting enzyme in cholesterol synthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase: HMG-CoA reductase), decrease the incidence of the disease (11, 12). These observations have led to an extensive and ongoing evaluation of statins as preventive treatments for Alzheimer's disease (13-16).Mevalonate, a cholesterol precursor, the synthesis of which is blocked by statins, is converted into several bioactive compounds. Among these, the isoprenoids are of particular importance because, among other functions, they provide for the covalent addition of lipid moieties (prenylation) to regulatory proteins (17) and thereby affect critical cell functions. Prenylation by the mevalonate products farnesyl diphosphate and geranylgeranyl diphosphate, ...

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Section: Methodsmentioning

confidence: 99%

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Baudry

Liu

et al. 2004

Journal of Biological Chemistry

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“…Western Blot Analysis-Western blot analyses were performed as described previously (25). CTGF was detected in cellular homogenates.…”

Section: Methodsmentioning

confidence: 99%

Modulation of the Expression of Connective Tissue Growth Factor by Alterations of the Cytoskeleton

Ott

Iwanciw

Graneß

et al. 2003

Journal of Biological Chemistry

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Modulation of the cytoskeletal architecture was shown to regulate the expression of CTGF (connective tissue growth factor, CCN2). The microtubule disrupting agents nocodazole and colchicine strongly up-regulated CTGF expression, which was prevented upon stabilization of the microtubules by paclitaxel. As a consequence of microtubule disruption, RhoA was activated and the actin stress fibers were stabilized. Both effects were related to CTGF induction. Overexpression of constitutively active RhoA induced CTGF synthesis. Interference with RhoA signaling by simvastatin, toxinB, C3 toxin, and Y27632 prevented up-regulation of CTGF. Likewise, direct disintegration of the actin cytoskeleton by latrunculin B interfered with nocodazolemediated up-regulation of CTGF expression. Disassembly of actin fibers by cytochalasin D, however, unexpectedly increased CTGF expression indicating that the content of F-actin per se was not the major determinant for CTGF gene expression. Given the fact that cytochalasin D sequesters G-actin, a decrease in G-actin increased CTGF, while increased levels of Gactin corresponded to reduced CTGF expression. These data link alterations in the microtubule and actin cytoskeleton to the expression of CTGF and provide a molecular basis for the observation that CTGF is up-regulated in cells exposed to mechanical stress.

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“…In their active state, these proteins regulate important cellular functions including cell survival, proliferation, and differentiation, as well as cytoskeletal organization, by relaying extracellular ligand-stimulated signals to cytoplasmic signaling cascades (40,41). It is the inhibition of prenylation of the Rho-and Ras-related proteins by statins that is postulated to be responsible for some of the pleiotropic effects of this class of agents (42,43).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the concentration of simvastatin considered effective for modulating cardiomyocyte proliferation was in the range of 10-20 M (44) and the concentration required to influence apoptosis of malignant lung epithelial cell lines ranged from 8.4 M to 45.4 M depending on the cell line (45). Similarly, numerous other studies with mesenchymal cells utilized concentrations in the range of 1-10 M for modulation of various cellular functions, including the expression of growth factors and the production of various extracellular matrix molecules (42).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin

Louneva¹,

Huaman²,

Fertala³

et al. 2006

Arthritis & Rheumatism

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Objective. To examine whether statins are capable of modulating collagen gene expression in cultured systemic sclerosis dermal fibroblasts.Methods. Cultured dermal fibroblasts from 3 patients with diffuse systemic sclerosis of recent onset were treated with 5 M and 10 M of simvastatin for 3 or 4 days. Morphologic features, cytotoxicity, and type I collagen production and messenger RNA (mRNA) levels in the fibroblasts were examined. The effects of mevalonate, geranylgeranyl pyrophosphate (GGPP), and farnesyl pyrophosphate (FPP), which are lipids downstream from the hydroxymethylglutaryl-coenzyme A block, were also examined. Transient transfections with COL1A1 promoter-reporter constructs and electrophoretic gel mobility shift assays were utilized to examine COL1A1 transcription and Sp1 and CCAAT-box binding factor (CBF) binding.Results. Simvastatin did not cause morphologic changes or cytotoxicity in the fibroblasts, even after 4 days of treatment. Type I collagen production and mRNA levels showed a potent and dose-related inhibition following 3 and 4 days of treatment. The inhibition of collagen gene expression by simvastatin was completely reversed by mevalonate and GGPP, but not by FPP. The statin effects occurred at the transcriptional level and involved the proximal COL1A1 promoter region encompassing ؊174 bp. A significant reduction in Sp1 and CBF binding activity was also found in simvastatin-treated cells.

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Rho‐dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins)

Cited by 124 publications

References 50 publications

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Modulation of the Expression of Connective Tissue Growth Factor by Alterations of the Cytoskeleton

Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin

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