title: SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD.
abstract: Sirtuin1 (SIRT1), a protein/histone deacetylase, protects against the development of pulmonary emphysema. However, the molecular mechanisms underlying this observation remain elusive. The imbalance of tissue inhibitor of matrix metalloproteinases (TIMPs)/matrix metalloproteinases (MMPs) plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. We hypothesized that SIRT1 protects against emphysema by redressing the imbalance between MMPs and TIMPs. To test this hypothesis, SIRT1-deficient and overexpressing/transgenic mice were exposed to cigarette smoke (CS). The protein level and activity of MMP-9 were increased in lungs of SIRT1-deficient mice exposed to CS compared with wild-type (WT) littermates, and these effects were attenuated by SIRT1 overexpression. SIRT1 deficiency decreased the level of TIMP-1, which was augmented in SIRT1 transgenic mice compared with WT littermates by CS. However, the level of MMP-2, MMP-12, TIMP-2, TIMP-3, or TIMP-4 was not altered by SIRT1 in response to CS exposure. SIRT1 reduction was associated with imbalance of TIMP-1 and MMP-9 in lungs of smokers and COPD patients. Mass spectrometry and immunoprecipitation analyses revealed that TIMP-1 acetylation on specific lysine residues was increased, whereas its interaction with SIRT1 and MMP-9 was reduced in mouse lungs with emphysema, as well as in lungs of smokers and COPD patients. SIRT1 deficiency increased CS-induced TIMP-1 acetylation, and these effects were attenuated by SIRT1 overexpression. These results suggest that SIRT1 protects against COPD/emphysema, in part, via redressing the TIMP-1/MMP-9 imbalance involving TIMP-1 deacetylation. Thus redressing the TIMP-1/MMP-9 imbalance by pharmacological activation of SIRT1 is an attractive approach in the intervention of COPD.
authors.affiliation: Dept. of Environmental Medicine, Univ. of Rochester Medical Center, Box 850, 601 Elmwood Ave., Rochester, NY 14642. irfan_rahman@urmc.rochester.edu.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Jae-woong
authors.initials: JW
authors.lastname: Hwang
authors.forename: Isaac K
authors.initials: IK
authors.lastname: Sundar
authors.forename: Alan E
authors.initials: AE
authors.lastname: Friedman
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Vuokko L
authors.initials: VL
authors.lastname: Kinnula
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004646:Emphysema / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: C560822:TIMP1 protein, human; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D014028:Tobacco Smoke Pollution; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: COPD; MMPs; SIRT1; TIMPs; cigarette smoke; emphysema
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