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.

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

“…For example, in chronic obstructive pulmonary disorder, SIRT1 exerts a protective effect, partially because of its capacity to down-regulate MMP9 (49), and modulating NFkB activity during the disease (48). In addition to the known function of SIRT1 in repressing MMP9 in macrophages and monocytes (49), we demonstrated that SIRT1 represses MMP13, as well as MMP3 and -8, in chondrocytes. Thus, suggesting that part of the SIRT1 anti-inflammatory function is to repress the expression of these matrix-degrading enzymes, as was demonstrated here both in vitro and in vivo.…”

“…The results presented here show that SIRT1 represses LEF1 gene expression, which activates MMP13 gene expression. Studies have shown that SIRT1 can demonstrate a broad antiinflammatory function in a variety of tissues (44)(45)(46)(47)(48)(49). For example, in chronic obstructive pulmonary disorder, SIRT1 exerts a protective effect, partially because of its capacity to down-regulate MMP9 (49), and modulating NFkB activity during the disease (48).…”

Microglial Activation in Stroke: Therapeutic Targets

“…205 Conversely, SIRT1 inhibition or depletion in macrophage cultures has been shown to increase MMP-9 expression and TNF␣ secretion via promotion of NF-B transcriptional activity. 206,207 Cerebral ischemia results in altered SIRT1 protein and activity levels in brain. 208 Sirtuin activity is reduced within the first 6 hours after ischemic injury, but is then is increased at 12 and 24 hours.…”

Combined Exercise and Insulin-Like Growth Factor-1 Supplementation Induces Neurogenesis in Old Rats, but Do Not Attenuate Age-Associated DNA Damage

“…47,48 The oxidative stress-related changes might be associated with sirtuins, because they can be modulated by oxidative challenges. [49][50][51] Aerobic exercise, which is often used to study the effects of physical activity on brain function, decreases the level of circulating IGF-1 with exercise of moderate intensity and long duration 52 ; however, the findings of Trejo and co-workers 53 on exercising in wild-type and mutant mice with low levels of serum IGF-1 show the complexity of IGF-1 in exercise physiology.…”