stilbenes and Cicatrix--Hypertrophic

Sirtuin1 (SIRT1), the founding member of mammalian class III histone deacetylases, is reported to be a drug target involved in fibrotic diseases. However, whether it is an effective drug target in hypertrophic scar treatment is still not known.. In the present study, we observed that SIRT1 localized to both the epidermis and the dermis of skin tissues by immunohistochemistry. After knock-down of SIRT1 by shRNA or up-regulating SIRT1 by resveratrol, the expression of α-SMA, Col1 and Col3 in fibroblasts were detected by western blots. A mouse excision wound healing model was used to observe the changes in collagen fibre associated with the different expression levels of SIRT1.. SIRT1 expression was inhibited in hypertrophic scar tissue. The down-regulation of SIRT1 resulted in an increased expression of α-SMA, Col1 and Col3 in hypertrophic scar-derived fibroblasts. In contrast, the up-regulation of SIRT1 not only inhibited the expression of α-SMA, Col1 and Col3 in hypertrophic scar-derived fibroblasts but also blocked the activation of TGFβ1-induced normal skin-derived fibroblasts. In the mouse model of wound healing, the deletion of SIRT1 resulted in denser collagen fibres and a more disordered structure, whereas resveratrol treatment led to a more organized and thinner collagen fibre, which was similar to that observed during normal wound healing.. The results revealed that SIRT1 negatively regulates TGFβ1-induced fibroblast activation and inhibits excessive scar formation and is, therefore, a promising drug target for hypertrophic scar formation.

Topics: Animals; Cells, Cultured; Cicatrix, Hypertrophic; Disease Models, Animal; Humans; Mice; Mice, Inbred BALB C; Resveratrol; RNA, Small Interfering; Sirtuin 1; Stilbenes

Hypertrophic scar (HS) is a dermal fibroproliferative disorder characterized by excessive deposition of extracellular matrix. Here, to investigate the regulative effects of resveratrol, a natural antioxidant compound, on fibroblasts from human skin HS tissue, a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the inhibitory effect of resveratrol on cells. Cellcycle progression and apoptosis were measured by flow cytometry and Hoechst 33258 staining respectively. The hydroxyproline content and mRNA expression levels of type I and III procollagen were measured separately by ELISA and reverse transcription-polymerase chain reaction (RT-PCR). The results indicated that resveratrol significantly inhibited cell growth, arresting the cell cycle at the G1 phase and inducing apoptosis in the fibroblasts, decreasing hydroxyproline (or collagen) levels, and downregulating the expression levels of type I and III procollagen mRNA. Taken together, these data indicate that resveratrol-mediated reduction of collagen in fibroblasts is at least partially effected by causing inhibitory cell growth, cellcycle arrest, and apoptosis, and they suggest that resveratrol is a potential agent for HS treatment.

Topics: Apoptosis; Cell Cycle; Cell Proliferation; Cicatrix, Hypertrophic; Collagen Type I; Collagen Type III; Dose-Response Relationship, Drug; Female; Fibroblasts; Gene Expression Regulation; Humans; Hydroxyproline; Resveratrol; RNA, Messenger; Stilbenes; Young Adult