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-β2 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.
Highlights
Type I collagen is the major component of extracellular matrix of nearly every human organ and constitutes the most abundant form of collagen in the human body
Our study indicates that Valproic acid (VPA) is an effective inhibitor of collagen production via the disruption of both steady-state and TGF-β regulatory pathways mediated in part by Smads
To demonstrate that VPA regulates Col1a1 at the transcriptional level, conjunctival fibroblasts were transfected with a reporter plasmid driven by the Col1a1 promoter followed by treatment with 300 μg/ml VPA
Summary
Type I collagen is the major component of extracellular matrix of nearly every human organ and constitutes the most abundant form of collagen in the human body. In response to injury or certain diseases, collagen production facilitates the restoration of tissue homeostasis and normal physiological functions [1]. At times, this tissue repair response may be exaggerated, resulting in fibrosis or scarring. Accumulation of type I collagen is prevalent in many tumours and associated with increased risk of metastasis and poor prognosis [2]. In some surgeries such as glaucoma filtration surgery (GFS), scarring is implicated to be the main cause of surgical failure [3]. The modulation of type I collagen production in these pathological contexts is of utmost biological and clinical importance
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