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Connective tissue growth factor expression and induction by transforming growth factor-beta is abrogated by simvastatin via a Rho signaling mechanism.
Am J Physiol Lung Cell Mol Physiol. 2004 Dec; 287(6):L1323-32.AJ

Abstract

Connective tissue growth factor (CTGF), a potent profibrotic mediator, acts downstream and in concert with transforming growth factor (TGF)-beta to drive fibrogenesis. Significant upregulation of CTGF has been reported in fibrogenic diseases, including idiopathic pulmonary fibrosis (IPF), and is partly responsible for associated excessive fibroblast proliferation and extracellular matrix deposition, but no effective therapy exists for averting such fibrogeneic events. Simvastatin has reported putative antifibrotic actions in renal fibroblasts; this study explores such actions on human IPF-derived and normal lung fibroblasts and examines associated driving mechanisms. Simvastatin reduces basal CTGF gene and protein expression in all fibroblast lines, overriding TGF-beta induction through inhibition of the cholesterol synthesis pathway. Signaling pathways driving simvastatin's effects on CTGF/TGF-beta interaction were evaluated using transient reporter transfection of a CTGF promoter construct. Inhibition of CTGF promoter activity by simvastatin was most marked at 10 muM concentration, reducing activity by 76.2 and 51.8% over TGF-beta-stimulated cultures in IPF and normal fibroblasts, respectively. We also show that geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate, induces CTGF promoter activity following simvastatin inhibition by 55.3 and 31.1% over GGPP-negative cultures in IMR90 and IPF-derived fibroblasts, respectively, implicating small GTPase Rho involvement rather than Ras in these effects. Indeed, the specific Rho inhibitor C3 exotoxin significantly (P < 0.05) suppressed TGF-beta-induced CTGF promoter activity in transfected lung fibroblasts, a finding further supported by transfection of dominant-negative and constitutively active RhoA constructs, thus demonstrating that simvastatin through a Rho signaling mechanism in lung fibroblasts can modulate CTGF expression and interaction with TGF-beta.

Authors+Show Affiliations

Lung Research, Institute of Science and Technology in Medicine, University Hospital of North Staffordshire/Keele University, Stoke on Trent, United Kingdom. keira_watts@yahoo.co.ukNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15298857

Citation

Watts, Keira L., and Monica A. Spiteri. "Connective Tissue Growth Factor Expression and Induction By Transforming Growth Factor-beta Is Abrogated By Simvastatin Via a Rho Signaling Mechanism." American Journal of Physiology. Lung Cellular and Molecular Physiology, vol. 287, no. 6, 2004, pp. L1323-32.
Watts KL, Spiteri MA. Connective tissue growth factor expression and induction by transforming growth factor-beta is abrogated by simvastatin via a Rho signaling mechanism. Am J Physiol Lung Cell Mol Physiol. 2004;287(6):L1323-32.
Watts, K. L., & Spiteri, M. A. (2004). Connective tissue growth factor expression and induction by transforming growth factor-beta is abrogated by simvastatin via a Rho signaling mechanism. American Journal of Physiology. Lung Cellular and Molecular Physiology, 287(6), L1323-32.
Watts KL, Spiteri MA. Connective Tissue Growth Factor Expression and Induction By Transforming Growth Factor-beta Is Abrogated By Simvastatin Via a Rho Signaling Mechanism. Am J Physiol Lung Cell Mol Physiol. 2004;287(6):L1323-32. PubMed PMID: 15298857.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Connective tissue growth factor expression and induction by transforming growth factor-beta is abrogated by simvastatin via a Rho signaling mechanism. AU - Watts,Keira L, AU - Spiteri,Monica A, Y1 - 2004/08/06/ PY - 2004/8/10/pubmed PY - 2005/1/13/medline PY - 2004/8/10/entrez SP - L1323 EP - 32 JF - American journal of physiology. Lung cellular and molecular physiology JO - Am J Physiol Lung Cell Mol Physiol VL - 287 IS - 6 N2 - Connective tissue growth factor (CTGF), a potent profibrotic mediator, acts downstream and in concert with transforming growth factor (TGF)-beta to drive fibrogenesis. Significant upregulation of CTGF has been reported in fibrogenic diseases, including idiopathic pulmonary fibrosis (IPF), and is partly responsible for associated excessive fibroblast proliferation and extracellular matrix deposition, but no effective therapy exists for averting such fibrogeneic events. Simvastatin has reported putative antifibrotic actions in renal fibroblasts; this study explores such actions on human IPF-derived and normal lung fibroblasts and examines associated driving mechanisms. Simvastatin reduces basal CTGF gene and protein expression in all fibroblast lines, overriding TGF-beta induction through inhibition of the cholesterol synthesis pathway. Signaling pathways driving simvastatin's effects on CTGF/TGF-beta interaction were evaluated using transient reporter transfection of a CTGF promoter construct. Inhibition of CTGF promoter activity by simvastatin was most marked at 10 muM concentration, reducing activity by 76.2 and 51.8% over TGF-beta-stimulated cultures in IPF and normal fibroblasts, respectively. We also show that geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate, induces CTGF promoter activity following simvastatin inhibition by 55.3 and 31.1% over GGPP-negative cultures in IMR90 and IPF-derived fibroblasts, respectively, implicating small GTPase Rho involvement rather than Ras in these effects. Indeed, the specific Rho inhibitor C3 exotoxin significantly (P < 0.05) suppressed TGF-beta-induced CTGF promoter activity in transfected lung fibroblasts, a finding further supported by transfection of dominant-negative and constitutively active RhoA constructs, thus demonstrating that simvastatin through a Rho signaling mechanism in lung fibroblasts can modulate CTGF expression and interaction with TGF-beta. SN - 1040-0605 UR - https://www.unboundmedicine.com/medline/citation/15298857/Connective_tissue_growth_factor_expression_and_induction_by_transforming_growth_factor_beta_is_abrogated_by_simvastatin_via_a_Rho_signaling_mechanism_ L2 - https://journals.physiology.org/doi/10.1152/ajplung.00447.2003?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -