Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 312, Issue 1, Pages L68-L78Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00188.2016
Keywords
DNA damage; fibroblasts; pulmonary fibrosis; SIRT3
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Funding
- National Heart, Lung, and Blood Institute [HL-117041, HL-111455, 1R56HL127395]
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Myofibroblast differentiation is a key process in the pathogenesis of fibrotic diseases. Transforming growth factor-beta(1) (TGF-beta(1)) is a powerful inducer of myofibroblast differentiation and is implicated in pathogenesis of tissue fibrosis. This study was undertaken to determine the role of mitochondrial deacetylase SIRT3 in TGF-beta(1)-induced myofibroblast differentiation in vitro and lung fibrosis in vivo. Treatment of human lung fibroblasts with TGF-beta(1) resulted in increased expression of fibrosis markers, smooth muscle alpha-actin (alpha-SMA), collagen-1, and fibronectin. TGF-beta(1) treatment also caused depletion of endogenous SIRT3, which paralleled with increased production of reactive oxygen species (ROS), DNA damage, and subsequent reduction in levels of 8-oxoguanine DNA glycosylase (OGG1), an enzyme that hydrolyzes oxidized guanine (8-oxo-dG) and thus protects DNA from oxidative damage. Overexpression of SIRT3 by adenovirus-mediated transduction reversed the effects of TGF-beta(1) on ROS production and mitochondrial DNA damage and inhibited TGF-beta(1)-induced myofibroblast differentiation. To determine the antifibrotic role of SIRT3 in vivo, we used the bleomycin-induced mouse model of pulmonary fibrosis. Compared with wild-type controls, Sirt3-knockout mice showed exacerbated fibrosis after intratracheal instillation of bleomycin. Increased lung fibrosis was associated with decreased levels of OGG1 and concomitant accumulation of 8-oxo-dG and increased mitochondrial DNA damage. In contrast, the transgenic mice with whole body Sirt3 overexpression were protected from bleomycin-induced mtDNA damage and development of lung fibrosis. These data demonstrate a critical role of SIRT3 in the control of myofibroblast differentiation and lung fibrosis.
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