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

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 6

SIRT1 protects against CS- or elastase-induced increase in lung SA–β-gal activity.

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SIRT1 protects against CS- or elastase-induced increase in lung SA–β-gal...
(A) CS exposure for 3 days increased lung SA–β-gal activity (arrows). (B) Whereas SA–β-gal activity was increased by Sirt1 deficiency when exposed to CS for 6 months, this was not observed in lungs of Sirt1 Tg mice. (C) SRT1720 administration prior to emphysema development attenuated SA–β-gal activity in lungs of WT, but not Sirt1+/–, mice in response to elastase exposure. (D) SRT1720 administration after emphysema development for 2 weeks ameliorated elastase-induced increase in lung SA–β-gal activity (arrows). (E and F). SA–β-gal activity was increased in lungs of Epi-Sirt1–/–, but not Mac-Sirt1–/–, mice compared with their WT littermates after elastase injection. Original magnification, ×200; ×400 (inset). Scale bars: 100 μm. SA–β-gal activity is expressed as 4-MU fluorescence normalized to protein content (see Methods). n = 3–4 per group. ‡P < 0.05 versus air; *P < 0.05, **P < 0.01, §P < 0.001 versus saline; #P < 0.05 versus WT; ††P < 0.01 versus vehicle.