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Abstract #21780 Published in IGR 10-3
Lovastatin inhibits TGF-β-induced myofibroblast transdifferentiation in human tenon fibroblasts
Meyer-Ter-Vehn T; Katzenberger B; Han H; Grehn F; Schlunck GInvestigative Ophthalmology and Visual Science 2008; 49: 3955-3960
PURPOSE: The transdifferentiation of Tenon fibroblasts to myofibroblasts is a pivotal step in filtering bleb scarring. It is mediated by the cytokine TGF-β, Rho-dependent contractility, and cell-matrix interactions in an interdependent fashion. HMG-CoA-reductase inhibitors (statins) have been shown to inhibit Rho-GTPase signaling; therefore, the authors studied the influence of lovastatin on TGF-β-mediated myofibroblast transdifferentiation to assess the potential use of statins in wound healing modulation. METHODS: Human Tenon fibroblasts were grown in culture, pretreated with lovastatin, lovastatin and mevalonate, or specific inhibitors of farnesyl transferase or geranylgeranyl transferase and were stimulated with TGF-β1.α-Smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF) transcription were assessed by real-time PCR. α-SMA protein expression and localization were studied by Western blot and confocal immunofluorescence microscopy. Cell contractility was determined in collagen gel contraction assays. Phosphorylation of the signaling proteins Smad-2/3 and p38 were detected by Western blot, and Smad-2/3 localization was determined by confocal immunofluorescence microscopy. RESULTS: Lovastatin inhibited TGF-β-induced CTGF transcription, α-SMA expression and incorporation into actin stress fibers, and subsequent collagen gel contraction. These effects were reversed by mevalonate. The inhibition of geranylgeranyl transferase but not farnesyl transferase blocked TGF-β-induced α-SMA expression. Lovastatin decreased TGF-β-induced p38 activation, whereas Smad-2/3 phosphorylation and nuclear translocation were preserved. CONCLUSIONS: Lovastatin inhibits TGF-β-induced myofibroblast transdifferentiation in human Tenon fibroblasts, most likely by interfering with Rho-signaling. Statins may, therefore, serve to inhibit scarring after filtering glaucoma surgery.
Dr. T. Meyer-Ter-Vehn, Department of Ophthalmology, University of Würzburg, Würzburg, Germany
Classification:
12.8.10 Woundhealing antifibrosis (Part of: 12 Surgical treatment > 12.8 Filtering surgery)
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
