SIRT1 modulates expression of matrix metalloproteinases in human dermal fibroblasts

Br J Dermatol. 2010 Oct;163(4):689-94. doi: 10.1111/j.1365-2133.2010.09825.x.

Abstract

Background: SIRT1, an NAD(+) -dependent histone/protein deacetylase, controls a broad range of cellular functions.

Objectives: We examined if SIRT1 is involved in the regulation of matrix metalloproteinase (MMP) expression in human dermal fibroblasts.

Methods: We studied the effect of inhibition of SIRT1 by specific inhibitor and small interfering RNA (siRNA) on MMP-1 and MMP-3 expression in human dermal fibroblasts.

Results: Treatment with a potent and selective inhibitor of SIRT1, EX-527, increased the basal expression levels of MMP-1 and MMP-3 proteins. Knockdown of endogenous SIRT1 by siRNA led to increased expression of MMP-1 and MMP-3 at both mRNA and protein levels. SIRT1 knockdown also upregulated MMP protein induction caused by an inflammatory cytokine, interleukin (IL)-1β. Moreover, treatment with a SIRT1 activator, resveratrol, significantly suppressed IL-1β-mediated induction of MMP-1, which was attenuated by pretreatment with EX-527. Finally, MMP-1 promoter activity was increased by EX-527 in cells treated with or without IL-1β.

Conclusions: Our findings suggest that SIRT1 exerts a negative regulatory role in the production of MMP-1 and MMP-3 in human dermal fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbazoles / pharmacology
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Matrix Metalloproteinase 1 / biosynthesis
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 3 / biosynthesis
  • Matrix Metalloproteinase 3 / genetics
  • Matrix Metalloproteinases / biosynthesis*
  • Matrix Metalloproteinases / genetics
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / physiology*
  • Skin / cytology
  • Skin / drug effects
  • Skin / enzymology*

Substances

  • 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
  • Carbazoles
  • Enzyme Inhibitors
  • RNA, Small Interfering
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 1
  • SIRT1 protein, human
  • Sirtuin 1