Please use this identifier to cite or link to this item: https://doi.org/10.1007/s00109-015-1358-z
Title: Valproic acid suppresses collagen by selective regulation of Smads in conjunctival fibrosis
Authors: Seet, L.-F 
Toh, L.Z
Finger, S.N
Chu, S.W.L
Stefanovic, B
Wong, T.T 
Keywords: alpha smooth muscle actin
beta actin
collagen type 1
messenger RNA
short hairpin RNA
Smad protein
Smad2 protein
Smad4 protein
Smad6 protein
tenascin
transforming growth factor beta2
valproic acid
collagen type 1
enzyme inhibitor
Smad protein
transforming growth factor beta2
valproic acid
animal cell
animal experiment
animal model
apoptosis
Article
cell differentiation
cell viability
collagen fiber
conjunctiva disease
conjunctival fibrosis
fibroblast
fibrosis
filtering operation
glaucoma
mouse
myofibroblast
nonhuman
phenotype
promoter region
protein expression
regulatory mechanism
steady state
wound healing
animal
C57BL mouse
cell culture
complication
conjunctiva
drug effects
fibrosis
gene expression regulation
genetics
glaucoma
metabolism
pathology
Animals
Cells, Cultured
Collagen Type I
Conjunctiva
Enzyme Inhibitors
Fibroblasts
Fibrosis
Gene Expression Regulation
Glaucoma
Mice
Mice, Inbred C57BL
Smad Proteins
Transforming Growth Factor beta2
Valproic Acid
Issue Date: 2016
Publisher: Springer Verlag
Citation: Seet, L.-F, Toh, L.Z, Finger, S.N, Chu, S.W.L, Stefanovic, B, Wong, T.T (2016). Valproic acid suppresses collagen by selective regulation of Smads in conjunctival fibrosis. Journal of Molecular Medicine 94 (3) : 321-334. ScholarBank@NUS Repository. https://doi.org/10.1007/s00109-015-1358-z
Rights: Attribution 4.0 International
Abstract: Abstract: Overproduction of type I collagen is associated with a wide range of fibrotic diseases as well as surgical failure such as in glaucoma filtration surgery (GFS). Its modulation is therefore of clinical importance. Valproic acid (VPA) is known to reduce collagen in a variety of tissues with unclear mechanism of action. In this report, we demonstrate that VPA inhibited collagen production in both conjunctival fibroblasts and the mouse model of GFS. In fibroblasts, VPA decreased type I collagen expression which intensified with longer drug exposure and suppressed steady-state type I collagen promoter activity. Moreover, VPA decreased Smad2, Smad3 and Smad4 but increased Smad6 expression with a similar intensity-exposure profile. Reduction of Smad3 using small hairpin RNA and/or overexpression of Smad6 resulted in decreased collagen expression which was exacerbated when VPA was simultaneously present. Furthermore, fibrogenic TGF-?2 failed to induce collagen when VPA was present, as opposed to the myofibroblast markers, beta-actin, alpha-smooth muscle actin and tenascin-C, which were elevated by TGF-β2. VPA suppressed p3TP-Lux luciferase activity and selectively rescued Smad6 expression from suppression by TGF-β2. Notably, SMAD6 overexpression reduced the effectiveness of TGF-β2 in inducing collagen expression. In corroboration, VPA inhibited type I collagen but increased Smad6 expression in the late phase of wound healing in the mouse model of GFS. Taken together, our data indicate that VPA has the capacity to effectively suppress both steady-state and fibrogenic activation of type I collagen expression by modulating Smad expression. Hence, VPA is potentially applicable as an anti-fibrotic therapeutic by targeting collagen. Key message: • VPA modulates type I collagen expression via members of the Smad family. •VPA suppresses Smad2, Smad3 and Smad4 but upregulates Smad6. •Smad3 and Smad6 are involved in VPA regulation of steady-state collagen expression. •Smad6 is involved in VPA modulation of TGF-β-stimulated collagen expression. •VPA reduces collagen and upregulates Smad6 in the mouse model of glaucoma filtration surgery. © 2015, The Author(s).
Source Title: Journal of Molecular Medicine
URI: https://scholarbank.nus.edu.sg/handle/10635/179594
ISSN: 0946-2716
DOI: 10.1007/s00109-015-1358-z
Rights: Attribution 4.0 International
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