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SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice
Hongwei Yao, … , Vuokko L. Kinnula, Irfan Rahman
Hongwei Yao, … , Vuokko L. Kinnula, Irfan Rahman
Published May 1, 2012
Citation Information: J Clin Invest. 2012;122(6):2032-2045. https://doi.org/10.1172/JCI60132.
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Research Article Pulmonology

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

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Abstract

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.

Authors

Hongwei Yao, Sangwoon Chung, Jae-woong Hwang, Saravanan Rajendrasozhan, Isaac K. Sundar, David A. Dean, Michael W. McBurney, Leonard Guarente, Wei Gu, Mikko Rönty, Vuokko L. Kinnula, Irfan Rahman

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Figure 11

Role of the SIRT1/FOXO3 pathway in protecting against emphysema.

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Role of the SIRT1/FOXO3 pathway in protecting against emphysema.
Lung le...
Lung level of SIRT1 is reduced in response to CS or oxidative/carbonyl stress, which leads to acetylation and degradation of FOXO3 and culminates in stress-induced premature senescence. The senescence of lung cells is a contributing factor to airspace enlargement and emphysema. NF-κB is also acetylated and activated in response to CS exposure as a result of SIRT1 reduction. However, inhibition of NF-κB–dependent lung inflammation does not prevent the progression of airspace enlargement. SIRT1 activation by overexpression and pharmacological means protects the lungs against cellular senescence and emphysematous changes.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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