SIRT1 modulates expression of matrix metalloproteinases in human dermal fibroblasts.
BACKGROUND
SIRT1, an NAD(+) -dependent histone/protein deacetylase, controls a broad range of cellular functions.


OBJECTIVE
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.
Ohguchi
K
K
Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan. kohguchi@giib.or.jp
Itoh
T
T
Akao
Y
Y
Inoue
H
H
Nozawa
Y
Y
Ito
M
M
D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*
C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; C447939:SIRT1 protein, human; D056564:Sirtuin 1