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

Abstract

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.

• Authors: Yuji Nakamaru, Chaitanya Vuppusetty, 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, Kazuhiro Ito
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 23 Issue 9 Pg. 2810-9 (Sep 2009) ISSN: 1530-6860 [Electronic] United States
• PMID: 19376817 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Smoke
• Hydrogen Peroxide
• Matrix Metalloproteinase 9
• SIRT1 protein, human
• Sirt1 protein, mouse
• Sirtuin 1
• Sirtuins

Topics

• Animals
• Cell Line
• Gene Expression Regulation
• Humans
• Hydrogen Peroxide
• Inflammation
• Lung (pathology)
• Macrophages
• Matrix Metalloproteinase 9 (analysis, genetics, metabolism)
• Mice
• Monocytes
• Oxidative Stress
• Promoter Regions, Genetic
• Pulmonary Disease, Chronic Obstructive (metabolism, pathology)
• Sirtuin 1
• Sirtuins (analysis, genetics, physiology)
• Smoke (adverse effects)
• Nicotiana