| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
is abrogated by simvastatin via a Rho signaling mechanism
Lung Research, Institute of Science and Technology in Medicine, University Hospital of North Staffordshire/Keele University, Stoke on Trent ST4 7NQ, Staffordshire, United Kingdom
Submitted 18 December 2003 ; accepted in final form 6 August 2004
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 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- induction through inhibition of the cholesterol synthesis pathway. Signaling pathways driving simvastatin's effects on CTGF/TGF- interaction were evaluated using transient reporter transfection of a CTGF promoter construct. Inhibition of CTGF promoter activity by simvastatin was most marked at 10 µM concentration, reducing activity by 76.2 and 51.8% over TGF--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--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-.
idiopathic pulmonary fibrosis; fibroblasts; statins; small GTPase
This article has been cited by other articles:
|
|
 |
|
  T. Meyer-ter-Vehn, B. Katzenberger, H. Han, F. Grehn, and G. Schlunck Lovastatin Inhibits TGF-{beta}-Induced Myofibroblast Transdifferentiation in Human Tenon Fibroblasts Invest. Ophthalmol. Vis. Sci., September 1, 2008; 49(9): 3955 - 3960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Gardner, S. M. Turner, A. Bautista, G. Lindwall, M. Awada, and M. K. Hellerstein Measurement of liver collagen synthesis by heavy water labeling: effects of profibrotic toxicants and antifibrotic interventions Am J Physiol Gastrointest Liver Physiol, June 1, 2007; 292(6): G1695 - G1705. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Huang, L. Taylor, B. Liu, J. Yu, and P. Polgar Modulation by bradykinin of angiotensin type 1 receptor-evoked RhoA activation of connective tissue growth factor expression in human lung fibroblasts Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1291 - L1299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Watts, E. M. Sampson, G. S. Schultz, and M. A. Spiteri Simvastatin Inhibits Growth Factor Expression and Modulates Profibrogenic Markers in Lung Fibroblasts Am. J. Respir. Cell Mol. Biol., April 1, 2005; 32(4): 290 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Hirschberg Wound Healing in the Kidney: Complex Interactions in Renal Interstitial Fibrogenesis J. Am. Soc. Nephrol., January 1, 2005; 16(1): 9 - 11. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
