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A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9

Yuji Nakamaru^*,1, Chaitanya Vuppusetty^*,1, Hiroo Wada, Jill C. Milne, Misako Ito^*, Christos Rossios^*, Mark Elliot, James Hogg, Sergei Kharitonov^*, Hajime Goto, Jean E. Bemis, Peter Elliott, Peter J. Barnes^* and Kazuhiro Ito^*,2

^* Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK;

Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, Japan;

Sirtris, a GSK company, Cambridge, Massachusetts, USA; and

The James Hogg–iCAPTURE Center for Cardiovascular and Pulmonary Research, University of British Columbia, St. Paul’s Hospital, Vancouver, British Columbia, Canada

² Correspondence: Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, UK. E-mail: k.ito{at}imperial.ac.uk

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. H₂O₂ 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.—Nakamaru, Y., Vuppusetty, C., Wada, H., Milne, J. C., Ito, M., Rossios, C., Elliot, M., Hogg, J., Kharitonov, S., Goto, H., Bemis, J. E., Elliott, P., Barnes, P. J., Ito, K. A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9.

Key Words: cigarette smoke • chronic obstructive pulmonary disease • COPD • oxidative stress • U937 cells