SIRT1 as a therapeutic target in inflammaging of the pulmonary disease

Rahman, Irfan; Kinnula, Vuokko L.; Gorbunova, Vera; Yao, Hongwei

doi:10.1016/j.ypmed.2011.11.014

Cited by 102 publications

(76 citation statements)

References 151 publications

(193 reference statements)

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“…Inflammation and cellular senescence are intertwined in the process of accelerated or premature lung aging (inflammaging) (71). The percentage of proinflammatory senescent type II cells expressing both p16 and phosphorylated NF-κB (i.e., senescence-associated secretory phenotype [SASP]) has been shown to be augmented in lungs of COPD patients compared with smokers and nonsmokers (33).…”

Section: Figurementioning

confidence: 99%

“…These findings highlight the mechanism of SIPS in the pathogenesis of COPD/emphysema. They also provide the rationale for a key and specific therapeutic target via pharmacological activation of SIRT1 in ameliorating/halting the progression of this diverse and complex debilitating disease (71,77). Hence, the activation of SIRT1 may prove a therapeutic intervention to prevent premature lung senescence/aging in COPD.…”

Section: Figurementioning

confidence: 99%

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SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Yao

Chung²,

Hwang³

et al. 2012

J. Clin. Invest.

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315

351

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Chronic obstructive pulmonary disease/emphysema (COPD/emphysema) is characterized by chronic inflammation and premature lung aging. Anti-aging sirtuin 1 (SIRT1), a NAD + -dependent protein/histone deacetylase, is reduced in lungs of patients with COPD. However, the molecular signals underlying the premature aging in lungs, and whether SIRT1 protects against cellular senescence and various pathophysiological alterations in emphysema, remain unknown. Here, we showed increased cellular senescence in lungs of COPD patients. SIRT1 activation by both genetic overexpression and a selective pharmacological activator, SRT1720, attenuated stress-induced premature cellular senescence and protected against emphysema induced by cigarette smoke and elastase in mice. Ablation of Sirt1 in airway epithelium, but not in myeloid cells, aggravated airspace enlargement, impaired lung function, and reduced exercise tolerance. These effects were due to the ability of SIRT1 to deacetylate the FOXO3 transcription factor, since Foxo3 deficiency diminished the protective effect of SRT1720 on cellular senescence and emphysematous changes. Inhibition of lung inflammation by an NF-κB/IKK2 inhibitor did not have any beneficial effect on emphysema. Thus, SIRT1 protects against emphysema through FOXO3-mediated reduction of cellular senescence, independently of inflammation. Activation of SIRT1 may be an attractive therapeutic strategy in COPD/emphysema.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Yao

Chung²,

Hwang³

et al. 2012

J. Clin. Invest.

Self Cite

315

351

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“…Targeted disruption of FOXO3 results in downregulation of these antioxidant genes in mouse lungs and increases the susceptibility for the development of COPD/emphysema (55). Yao and colleagues have shown that the SIRT1-FOXO3-mediated pathway is important in pathogenesis of COPD independent of the NF-jB pathway (116,184). Further studies on the SIRT1-FOXO3 pathway will elucidate the underlying mechanisms in response to oxidative/carbonyl stress, and will provide the possible therapeutic interventions in treatment of COPD based on SIRT1 activation.…”

mentioning

confidence: 99%

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

Sundar

Yao

Rahman

2013

Antioxidants & Redox Signaling

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162

107

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Significance: Chronic obstructive pulmonary disease (COPD) is predominantly a tobacco smoke-triggered disease with features of chronic low-grade systemic inflammation and aging (inflammaging) of the lung associated with steroid resistance induced by cigarette smoke (CS)-mediated oxidative stress. Oxidative stress induces various kinase signaling pathways leading to chromatin modifications (histone acetylation/deacetylation and histone methylation/demethylation) in inflammation, senescence, and steroid resistance. Recent Advances: Histone mono-, di-, or tri-methylation at lysine residues result in either gene activation (H3K4, H3K36, and H3K79) or repression (H3K9, H3K27, and H3K20). Cross-talk occurs between various epigenetic marks on histones and DNA methylation. Both CS and oxidants alter histone acetylation/deacetylation and methylation/ demethylation leading to enhanced proinflammatory gene expression. Chromatin modifications occur in lungs of patients with COPD. Histone deacetylase 2 (HDAC2) reduction (levels and activity) is associated with steroid resistance in response to oxidative stress. Critical Issues: Histone modifications are associated with DNA damage/repair and epigenomic instability as well as premature lung aging, which have implications in the pathogenesis of COPD. HDAC2/SIRTUIN1 (SIRT1)-dependent chromatin modifications are associated with DNA damage-induced inflammation and senescence in response to CS-mediated oxidative stress. Future Directions: Understanding CS/oxidative stress-mediated chromatin modifications and the cross-talk between histone acetylation and methylation will demonstrate the involvement of epigenetic regulation of chromatin remodeling in inflammaging. This will lead to identification of novel epigenetic-based therapies against COPD and other smoking-related lung diseases. Pharmacological activation of HDAC2/SIRT1 or reversal of their oxidative post-translational modifications may offer therapies for treatment of COPD and CS-related diseases based on epigenetic histone modifications.

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“…SIRT1 expression is decreased in the lung tissues from patients with COPD by oxidative stress and smoking [128] . Decreased SIRT1 expression results in the increased expression of proinflammatory cytokines due to NF-κB activation, and also results in the acceleration of cellular senescence mediated by the decrease of anti-senescent activity through FOXO3 [129] . Cellular senescence and emphysema were suppressed in SIRT1 transgenic mice by a FOXO3-mediated reduction of premature senescence in mice, while those are deteriorated in SITR1 knockout mice [130] .…”

Section: Chronic Obstructive Pulmonary Disease (Copd)mentioning

confidence: 99%

Autophagy and Cellular Senescence in Lung Diseases

Kuwano

Araya

Hara

et al. 2015

Journal of Biochemistry and Molecular Biology Research

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cells. The detailed molecular mechanism for regulation of autophagy and cellular senescence is complex and the role of autophagy and cellular senescence is overlap significantly. We review molecular mechanisms of autophagy and cellular senescence, and summarize the role of autophagy and cellular senescence in pulmonary disease pathogeneses. AUTOPHAGYAutophagy is a process of lysosomal self-degradation that helps maintain homeostatic balance between the synthesis, degradation and recycling of cellular proteins and organelles [1] . At the cellular level, auto-digestion takes place within lysosomes and proteasomes. Proteasomes are involved in the clearance of ubiquitin-conjugated soluble proteins, whereas autophagy delivers diverse cytoplasmic components to the lysosome, including soluble proteins, aggregateprone proteins, and organelles [2] . Autophagy is not simply machinery for amino acid supply in response to energy demand, it is an adaptive pathway of cytoprotection from cellular stresses, involving starvation, reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and microbe infection [2] . ABSTRACTAutophagy is a process of lysosomal self-degradation that helps maintain homeostatic balance between the synthesis, degradation and recycling of cellular proteins and organelles. In addition to nutrient starvation, a wide array of cellular stresses are also known to be strong inducers of autophagy, indicating that autophagy is not only simple amino acid supply machinery in response to energy demand but also a central component of the integrated stress response for cytoprotection. Since autophagy is an adaptive pathway of cytoprotection from cellular stresses, involving starvation, reactive oxygen species, endoplasmic reticulum stress, and microbe infection, it is reasonable to suggest that autophagy is closely related with aging. Indeed, autophagy diminishes with aging and accelerated aging can be attributed to reduced autophagy. Cellular senescence is also one of the cellular stress responses as well as autophagy, and considered to be one of the processes of aging. Cellular senescence has been widely implicated in disease pathogenesis in terms of not only impaired cell repopulation but also aberrant cytokine secretions of senescence associated secretory phenotype, which may exert deleterious effects on the tissue microenvironment of neighboring

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SIRT1 as a therapeutic target in inflammaging of the pulmonary disease

Cited by 102 publications

References 151 publications

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

Autophagy and Cellular Senescence in Lung Diseases

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