K Ohguchi1, T Itoh, Y Akao, H Inoue, Y Nozawa, M Ito. 1. Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan. kohguchi@giib.or.jp
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.
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.
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