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

I. SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD. Am J Physiol Lung Cell Mol Physiol 305: L615-L624, 2013. First published September 13, 2013 doi:10.1152/ajplung.00249.2012, 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. SIRT1; cigarette smoke; MMPs; TIMPs; emphysema; COPD SIRTUIN1 (SIRT1), a type III histone/protein deacetylase, plays an important role in inflammation, stress resistance, and cellular senescence/aging through the deacetylation of histones, transcription factors, and signaling molecules. It is a redoxsensitive deacetylase that can be posttranslationally modified by oxidants and carbonyl stress, leading to proteasomal degradation (9,36,59). This may be one of the reasons for the reduction of SIRT1 level in peripheral lung tissues of smokers and patients with chronic obstructive pulmonary disease (COPD)/emphysema (36, 55). Recently, we have shown that SIRT1 protects against pulmonary emphysema in mice (55). However, the mechanisms of SIRT1 in preventing the progression of COPD/emphysema are not fully understood.The imbalance of tissue inhibitors of metalloproteinases (TIMPs)/matrix metalloproteinases (MMPs) in the lungs has been implicated in the d...

Hallmarks of the ageing lung

“…The relevance of protease imbalance for COPD pathogenesis is also reflected by hereditary deficiency of α 1 -antitrypsin or α 1 -antichymotrypsin, which not only impair cellular proteostasis but also drives emphysematous ECM remodelling in COPD [67]. Recent findings extend ECM alterations to dysregulated matrix metalloproteases (MMP) function in human COPD and cigarette smoke-induced mouse emphysema [128,129]. In line with this, mice with reduced expression of the ECM glycoprotein fibulin-4, due to a hypomorphic fibulin-4 allele, have been shown to spontaneously develop pulmonary emphysema, as characterised by airspace enlargement and altered protease/antiprotease activity in the lung [130].…”

MMP-9 genetic polymorphism may confer susceptibility to COPD

“…MMP-9 may affect airflow limitation through degradation of alveolar ECM and components of the basement membrane, thus resulting in emphysema (Elkington et al, 2011). As the major rate-limiting enzyme in the MMP family, MMP-9 and its inhibitory factor TIMP-1 play essential roles in remodeling airflows, and MMP-9 may contribute to inflammation and flow choking by increasing inflammatory corpuscles in the airway lumen or airway wall, damaging the epithelial/endothelial structure (Bourboulia and Stetler-Stevenson, 2010;Yao et al, 2013). Genetic polymorphisms of MMP-9 may affect the expression and activity of MMP-9.…”

Smoking, aging, and expression of proteins related to the FOXO3 signaling pathway in lung tissues

“…Previous studies on COPD have primarily focused on inflammation, oxidative stress, and the protease/anti-protease imbalance, which cannot explain the similarities between the clinical manifestations of COPD and aging (Yao et al, 2013). FOXO signaling pathways are important for regulating metabolism and life span in mammals.…”

“…In adults aged 40 years or more, COPD incidence increases significantly with increasing age, and age itself is a risk factor for COPD, independently of the number of cigarettes smoked per year (Burney et al, 2013;Daldoul et al, 2013). In lung tissues, peripheral blood mononuclear cells and alveolar macrophages from patients with COPD exhibit decreased expression of a variety of longevity-and aging-related molecules, including sirtuin 1 (SIRT1) and sirtuin 6, which belong to the class III histone deacetylase family, histone deacetylase 2, which belong to the class I histone deacetylases, senescence marker protein 30, and klotho (Yao et al, 2013;Hwang et al, 2014). These proteins are thought to exert antiaging effects, suggesting that longevity-and aging-related signaling pathways are related to pathophysiological changes in COPD.…”