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The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates
Fibrotic Responses by Targeting Transforming Growth Factor ? Signaling
#MMPMID25707573
Wei J
; Ghosh AK
; Chu H
; Fang F
; Hinchcliff ME
; Wang J
; Marangoni RG
; Varga J
Arthritis Rheumatol
2015[May]; 67
(5
): 1323-34
PMID25707573
show ga
OBJECTIVE: Persistent fibroblast activation underlies skin fibrosis in systemic
sclerosis (SSc), but the transcriptional and epigenetic mechanisms controlling
this process are not well understood. In view of the potent influence of
acetylation status governing tissue fibrosis, we undertook this study to
investigate the expression of the antiaging deacetylase enzyme sirtuin 1 (SIRT1)
in SSc and its effects on fibrotic responses in vitro and in vivo. METHODS:
Tissue expression of SIRTs was interrogated from publicly available genome-wide
expression data sets and by immunohistochemistry. The effects of SIRT1 on
modulating fibrotic responses, as well as the underlying mechanisms, were
examined in human and mouse fibroblasts in culture and in an experimental
fibrosis model in the mouse. RESULTS: Analysis of transcriptome data revealed a
selective reduction of SIRT1 messenger RNA (mRNA) levels in SSc skin biopsy
samples as well as a negative correlation of SIRT1 mRNA with the skin score.
Cellular SIRT1 levels were suppressed in normal fibroblasts exposed to hypoxia or
platelet-derived growth factor and were constitutively down-regulated in SSc
fibroblasts. Activation of SIRT1 attenuated fibrotic responses in skin
fibroblasts and skin organ cultures, while genetic or pharmacologic inhibition of
SIRT1 had profibrotic effects. The antifibrotic effects of SIRT1 were due in part
to decreased expression and function of the acetyltransferase p300. In mice,
experimentally induced skin fibrosis was accompanied by reduced SIRT1 expression
in lesional tissue fibroblasts, and both fibrosis and loss of SIRT1 in these mice
were mitigated by treatment with a SIRT1 activator. CONCLUSION: SIRT1 has
antifibrotic effects, and its reduced tissue expression in patients with SSc
might have a direct causal role in progression of fibrosis. Pharmacologic
modulation of SIRT1 in these patients therefore might represent a potential
treatment strategy.
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