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, is abrogated by Simvastatin via a Rho signalling mechanism
1 University Hospital of North Staffordshire, Institute of Science and Technology in Medicine, Stoke on Trent, Staffordshire, United Kingdom
* To whom correspondence should be addressed. E-mail: keira_watts{at}yahoo.co.uk.
Connective Tissue Growth Factor (CTGF) a potent, profibrotic mediator acts downstream and in concert with Transforming Growth Factor (TGF)
, 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 (ECM) deposition. No effective therapy exists for averting such fibrogeneic events. Simvastatin is reported to have putative antifibrotic actions in renal fibroblasts. This present work explores such actions on human IPF-derived and normal lung fibroblasts, and examines associated driving mechanisms. Simvastatin reduces
basal gene and protein expression of CTGF in both fibroblast lines and overrides TGF induction in a concentration-dependent manner through inhibition of the
cholesterol synthesis pathway. Signalling pathways driving the effects of Simvastatin on CTGF-TGF interaction are evaluated using transient reporter transfections of a plasmid construct containing the CTGF promoter. We document inhibition of CTGF promoter activity by Simvastatin, most marked at 10µM concentration to give rise to a 76.2% and a 51.8% reduction over TGF- stimulated cultures in IPF and normal fibroblasts respectively. In separate studies we show that geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP), 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-induced CTGF promoter activity in transfected lung fibroblasts; a finding further supported by transfection of dominant-negative and constitutively active RhoA constructs. These data confirm that CTGF expression, and its interaction with TGF can be modulated by Simvastatin through a Rho signalling mechanism in lung fibroblasts.
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