Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-κB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging

Yang, Se‐Ran; Wright, J. O. R. A. E.; Bauter, Mark R.; Seweryniak, Kathryn E.; Kode, Aruna; Rahman, Irfan

doi:10.1152/ajplung.00308.2006

Cited by 366 publications

(407 citation statements)

References 35 publications

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“…NF B activity has previously been shown to be inhibited by Sirt1 (23)(24)(25). We confirmed such inhibition of NF B in embryonic fibroblasts derived from Sirt1-tg mice.…”

Section: Discussionsupporting

confidence: 84%

“…IL-6 and TNF␣ are regulated by NF B, which in turn is activated by dietary lipids through the Toll-like receptor TLR4 (5). Interestingly, Sirt1 has been described to inhibit NF B activity (23)(24)(25). To evaluate whether NF B is down-modulated by Sirt1 in our mouse model, we performed the following in vivo and in vitro assays.…”

Section: Transgenic Sirt1 Mice Are Protected From Hepatic Inflammationmentioning

confidence: 99%

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Sirt1 protects against high-fat diet-induced metabolic damage

Pfluger

Herranz

Velasco-Miguel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

846

777

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The identification of new pharmacological approaches to effectively prevent, treat, and cure the metabolic syndrome is of crucial importance. Excessive exposure to dietary lipids causes inflammatory responses, deranges the homeostasis of cellular metabolism, and is believed to constitute a key initiator of the metabolic syndrome. Mammalian Sirt1 is a protein deacetylase that has been involved in resveratrol-mediated protection from high-fat dietinduced metabolic damage, but direct proof for the implication of Sirt1 has remained elusive. Here, we report that mice with moderate overexpression of Sirt1 under the control of its natural promoter exhibit fat mass gain similar to wild-type controls when exposed to a high-fat diet. Higher energy expenditure appears to be compensated by a parallel increase in food intake. Interestingly, transgenic Sirt1 mice under a high-fat diet show lower lipidinduced inflammation along with better glucose tolerance, and are almost entirely protected from hepatic steatosis. We present data indicating that such beneficial effects of Sirt1 are due to at least two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via stimulation of PGC1␣, and lower activation of proinflammatory cytokines, such as TNF␣ and IL-6, via downmodulation of NF B activity. Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet.inflammation ͉ metabolism ͉ NF B ͉ sirtuins ͉ steatosis D riven by the need for potent and safe options to treat obesity, diabetes, and the metabolic syndrome, numerous efforts are currently underway to achieve a better understanding of the molecular networks controlling cellular glucose, lipid, and energy metabolism (1-3). It is generally accepted that gene-environment interactions (such as the effect of high-fat diets on the molecular pathways that maintain energy homeostasis) play a key role in the pathogenesis of the metabolic syndrome (4). Intriguingly, several reports recently showed that specific dietary fatty acids can directly activate Toll-like receptors, which are better known as components of the innate immune system recognizing bacteria-derived fatty acids (5-7). The resulting immune response promotes the systemic activation of proinflammatory pathways including NF B, TNF␣, or IL-6 (5, 6). This chain of events is believed to ultimately lead to insulin resistance, setting in motion the vicious cycle of the metabolic syndrome (8).Recently, a series of studies in several organisms revealed multiple important links of the Sirtuin family of proteins with energy metabolism and inflammation (9-11). Also known as silent information regulator 2 (Sir2)-related enzymes, the Sirtuins have been well conserved throughout evolution and represent a family of nicotinamide adenine dinucleotide-dependent enzymes that deacetylate residues of acetylated lysine. The mammalian sirtuins Sirt1-Sirt7 are implicated in a number of cellular and physiological functions including gene sil...

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“…NF B activity has previously been shown to be inhibited by Sirt1 (23)(24)(25). We confirmed such inhibition of NF B in embryonic fibroblasts derived from Sirt1-tg mice.…”

Section: Discussionsupporting

confidence: 84%

Section: Transgenic Sirt1 Mice Are Protected From Hepatic Inflammationmentioning

confidence: 99%

Sirt1 protects against high-fat diet-induced metabolic damage

Pfluger

Herranz

Velasco-Miguel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

846

777

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“…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).…”

Section: Sirt1 Represses Mmp13 Gene Expression 3123mentioning

confidence: 99%

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

et al. 2017

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Reduced SIRT1 activity and levels during osteoarthritis (OA) promote gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase in matrix metalloproteinase (MMP) 13, partially because of enhanced LEF1 transcriptional activity. In this study, we assessed the role of SIRT1 in LEF1-mediated MMP13 gene expression in human OA chondrocytes. Results showed that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-1b, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression; however, overexpression of SIRT1 during IL-1b challenge impeded LEF1 levels and MMP13 gene expression. Previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, but we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mouse articular cartilage from Sirt1 2/2 presented increased LEF1 and MMP13 protein levels, similar to human OA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in human OA chondrocytes, which appears to be mediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression.-Elayyan, J., Lee, E.-J., Gabay, O., Smith, C. A., Qiq, O., Reich, E., Mobasheri, A., Henrotin, Y., Kimber, S. J., Dvir-Ginzberg, M. LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes. FASEB J. 31, 3116-3125 (2017). www.fasebj.orgArticular cartilage undergoes age-related degenerative changes leading to the joint disease osteoarthritis (OA). Gradual loss of hyaline joint cartilage during OA is evoked through chronic synovitis, which involves the accumulation of proinflammatory cytokines, as IL1b, TNF-a, and IL6 within the joint (1-5), subsequently leading to a steady increase in matrix metalloproteinases (MMPs) and a disintegrin and MMP with thrombospondin motifs (ADAMTS) proteins, which further promote cartilage destruction (6-12). Recent experimental attempts ABBREVIATIONS: ACAN, aggrecan gene; ADAMTS, a disintegrin and metalloproteinase with thrombospondin-like motifs; BMP, bone morphogenic protein; ChIP, chromatin immunoprecipitation; COL2A1, collagen-2 a-1 gene; FBS, fetal bovine serum; FGF, fibroblast growth factor; GDF, growth differentiation factor; GSK3b, glycogen synthase kinase-3b; hESC, human embryonic stem cell; KO, knockout; LEF, lymphoid enhancer factor; MMP, matrix metalloproteinase; NAM, nicotinamide adenine mononucleotide; OA, osteoarthritis; Res, resveratrol; qPCR, quantitative PCR; siRNA, small interfering RNA; SIRT1, silent mating type information regulation 2 homolog 1 (sirtuin-1); SOX9, sex-determining-region-on-the-Y-chromosome-relate...

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“…[21][22][23][24][25][26] Interestingly, Sirt1 expression in the lung is reduced in the elderly who are known to be particularly susceptible to PM-induced cardiopulmonary mortality. 24,33 In this study, we investigated the role of Sirt1 in PM-induced lung coagulation.…”

Section: Introductionmentioning

confidence: 99%

Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

Liu

Liang

et al. 2012

Blood

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Exposure to ambient particulate matter (PM) air pollution has been reported to trigger inflammation and thrombosis. However, molecular mechanisms underlying the modulation of coagulation pathways in PM-induced thrombosis remain largely unknown. We report here that Sirt1, a member of class III histone deacetylase, controls lung inflammation and coagulation after PM exposure. Sirt1 knock-out mice exhibited aggravated lung vascular leakage and inflammation after PM exposure, which was correlated with increased NF-B acetylation and activation. Furthermore, Sirt1 knock-out mice were highly susceptible to PM-induced lung coagulation as demonstrated by increased fibrin formation. The increased fibrin formation was associated with reduced tissue factor pathway inhibitor (TFPI) expression and increased plasminogen activator inhibitor-1 (PAI-1) activity in the lungs, thus favoring elevated coagulation and disrupted fibrinolysis responses. Thrombomodulin (TM), a central player of the anticoagulant protein C system, is regulated by Kruppel-like factor 2 (KLF2) at the transcriptional level. IntroductionExposure to ambient particulate matter (PM) air pollution has been associated with impaired pulmonary function and increased cardiovascular disease-related mortality including inflammation and thrombosis. 1-5 Acute exposure to increased ambient fine particulate matter Ͻ 2.5 m in diameter (PM 2.5 ) was estimated to cause the premature deaths of tens of thousands of people each year in the United States. 6 Urban particulate matter (UPM) PM 2.5, one of the major air pollutants closely monitored by the US Environmental Protection Agency (EPA), is a complex mixture of substances that are directly emitted into the air from dust, soot, smoke, and combustion. 6 To protect public health, the EPA issued the current 24-hour PM 2.5 standard at 35 g/m 3 . 6 Despite the enormous health problems caused by PM 2.5 exposure, there have been few studies performed to explore the molecular mechanisms of PM 2.5 -induced lung vascular dysfunction. PM 2.5 can reach deep in the lung to the small airway and alveoli, 6 and directly cause lung inflammation and injury. [7][8][9][10][11][12][13] The pulmonary complications may lead to detrimental effects on other organs, particularly cardiovascular dysfunction such as systemic microvascular dysfunction and thrombosis. 1,2,4,5,13 A recent study demonstrated that short-term UPM exposure triggered the activation of primary hemostasis in healthy mice, with no substantial secondary hemostasis activation, leading to arterial but not venous thrombosis. 5 Whereas another study showed that short-term UPM exposure may cause activation of coagulation responses and fibrin formation in the lung. 14 Tissue factor pathway inhibitor (TFPI) and plasminogen activator inhibitor-1 (PAI-1) play important roles in coagulation and fibrinolysis cascades, respectively. TFPI is an inhibitor of tissue factor (TF)-mediated coagulation responses. 15 PAI-1, on the other hand, is a major regulator of fibrinolysis, which functions by in...

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Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-κB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging

Cited by 366 publications

References 35 publications

Sirt1 protects against high-fat diet-induced metabolic damage

Sirt1 protects against high-fat diet-induced metabolic damage

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

Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

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