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SIRT3 prevents bleomycin induced lung fibrosis in mice by blocking mitochondrial DNA damage and ROS synthesis
Author(s) -
Bindu Samik
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.858.2
Subject(s) - myofibroblast , fibrosis , sirt3 , pulmonary fibrosis , dna damage , cancer research , biology , microbiology and biotechnology , cardiac fibrosis , pathology , medicine , nad+ kinase , sirtuin , biochemistry , dna , enzyme
Background and objective Tissue fibrosis is one of the most critical mechanisms in the pathogenesis of wide range of diseases. Fibrosis is also hallmark of organ dysfunction associated with aging. The process of fibrosis begins with transformation of fibroblast into myofibroblast, a cell which deposits extracellular matrix proteins and contributes to scar formation. Recently a group of NAD‐dependent deacetylases, called sirtuins, have been identified which are capable of regulating variety of cellular processes including extending lifespan of the organism. One of them is SIRT3, which is considered guardian of mitochondria. SIRT3 activation has been shown to ameliorate many aging‐associated diseases including development of metabolic syndrome, heart failure, hearing loss and cancer. SIRT3 activation has been also linked to longevity of the man. This study was undertaken to examine the role of SIRT3 in protecting the lungs from development of fibrosis. Methods and Results One of the most important contributors of tissue fibrosis is activation of transforming growth factor‐β (TGFβ1) signaling. To determine the role of SIRT3 in the induction of fibrosis, we treated human fetal lung fibroblasts (IMR‐90) with TGFβ1 (10ng/ml) for 48 hours. The results showed that there was a significant increase in the expression of fibrotic markers, including smooth muscle alpha‐actin (α‐SMA), type I collagen and fibronectin in TGFβ1 treated cells. TGFβ1 treatment also caused depletion of endogenous SIRT3 levels, which correlated with increased ROS production, DNA damage and subsequent reduction in levels of OGG1, a major DNA glycosylase which hydrolyzes oxidized‐guanine (8‐Oxo‐dG) and protects the DNA from oxidative damage. We also found increased expression of inflammosome markers such as caspase‐1, and IL‐1β in TGFβ1 treated IMR‐90 cells. These changes were blocked when cells were infected with adenovirus expressing wild‐type SIRT3, but not the mutant, thus suggesting the ability of SIRT3 to block transformation of lung fibroblasts to myofibroblasts. To determine the anti‐fibrotic effect of SIRT3 in vivo , we induced lung fibrosis in mice by intra‐tracheal instillation of bleomycin for three weeks. As compared to wild‐type controls, SIRT3‐KO mice showed exacerbated fibrosis after bleomycin treatment, as measured by increased expression of fibrotic marker collagen‐1 and inflammasome marker caspase 1 and subsequent decreased levels of OGG1. However, the transgenic mice having whole body SIRT3 over expression were protected from bleomycin‐induced lung fibrosis. Conclusion These data demonstrate that loss of mitochondrial SIRT3 promotes transformation of lung fibroblasts to myofibroblasts and development of lung fibrosis. Therefore, SIRT3 activation may be considered a medical therapy for the management of lung fibrosis. Support or Funding Information This study was supported by the NIH‐RO1 grants HL117041 and HL111455.