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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 Article has an altmetric score of 7

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 4

Foxo3 deficiency diminishes the protection of SRT1720 against elastase-induced emphysema.

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Foxo3 deficiency diminishes the protection of SRT1720 against elastase-...
(A and B) SRT1720-mediated protection against elastase-induced airspace enlargement was diminished in Foxo3–/– mice. (C and D) No effect of SRT1720 on lung compliance (C) or RL (D) was observed in Foxo3–/– mice exposed to elastase. (E and F) Treadmill running time (E) and arterial oxygen saturation (F) were decreased in Foxo3–/– mice in response to elastase intratracheal injection, which was not altered by SRT1720. H&E-stained images are representative of experiments from 3 separate mice. Original magnification, ×100. Scale bar: 100 μm. n = 3–4 per group. **P < 0.01, §P < 0.001 versus saline; ##P < 0.01 versus WT; †P < 0.05, ††P < 0.01 versus vehicle.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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