A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9.
Inappropriate elevation of matrix metalloproteinase-9 (MMP9) is reported to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The object of this study was to identify the molecular mechanism underlying this increase of MMP9 expression, and here we show that oxidative stress-dependent reduction of a protein deacetylase, SIRT1, known as a putative antiaging enzyme, causes elevation of MMP9 expression. A sirtuin inhibitor, splitomycin, and SIRT1 knockdown by RNA interference led an increase in MMP9 expression in human monocytic U937 cells and in primary sputum macrophages, which was detected by RT-PCR, Western blot, activity assay, and zymography. In fact, the SIRT1 level was significantly decreased in peripheral lungs of patients with COPD, and this increase was inversely correlated with MMP9 expression and MMP9 promoter activation detected by a chromatin immunoprecipitation assay. H(2)O(2) reduced SIRT1 expression and activity in U937 cells; furthermore, cigarette smoke exposure also caused reduction of SIRT1 expression in lung tissue of A/J mice, with concomitant elevation of MMP9. Intranasal treatment of a selective and novel SIRT1 small molecule activator, SRT2172, blocked the increase of MMP9 expression in the lung as well as pulmonary neutrophilia and the reduction in exercise tolerance. Thus, SIRT1 is a negative regulator of MMP9 expression, and SIRT1 activation is implicated as a novel therapeutic approach to treating chronic inflammatory diseases, in which MMP9 is abundant.
Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK.
Yuji
Y
Nakamaru
Chaitanya
C
Vuppusetty
Hiroo
H
Wada
Jill C
JC
Milne
Misako
M
Ito
Christos
C
Rossios
Mark
M
Elliot
James
J
Hogg
Sergei
S
Kharitonov
Hajime
H
Goto
Jean E
JE
Bemis
Peter
P
Elliott
Peter J
PJ
Barnes
Kazuhiro
K
Ito
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide; D007249:Inflammation; D008168:Lung / Q000473:pathology; D008264:Macrophages; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009000:Monocytes; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology; D056564:Sirtuin 1; D037761:Sirtuins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D012906:Smoke / Q000009:adverse effects; D014026:Nicotiana
D012906:Smoke; D006861:Hydrogen Peroxide; D020780:Matrix Metalloproteinase 9; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins