The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor β Signaling

Arthritis Rheumatol. 2015 May;67(5):1323-34. doi: 10.1002/art.39061.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Case-Control Studies
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Humans
  • Mice
  • Platelet-Derived Growth Factor / pharmacology
  • RNA, Messenger / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Resveratrol
  • Scleroderma, Systemic / genetics*
  • Scleroderma, Systemic / metabolism
  • Signal Transduction
  • Sirtuin 1 / genetics*
  • Sirtuin 1 / metabolism
  • Skin / cytology
  • Smad Proteins / metabolism
  • Stilbenes / pharmacology
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • p300-CBP Transcription Factors / genetics*
  • p300-CBP Transcription Factors / metabolism

Substances

  • Enzyme Inhibitors
  • Platelet-Derived Growth Factor
  • RNA, Messenger
  • Smad Proteins
  • Stilbenes
  • Transforming Growth Factor beta
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Sirtuin 1
  • Resveratrol