SIRT3 blocks myofibroblast differentiation and pulmonary fibrosis by preventing mitochondrial DNA damage.
Myofibroblast differentiation is a key process in the pathogenesis of fibrotic diseases. Transforming growth factor-β1(TGF-β1) 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-β1-induced myofibroblast differentiation in vitro and lung fibrosis in vivo. Treatment of human lung fibroblasts with TGF-β1resulted in increased expression of fibrosis markers, smooth muscle α-actin (α-SMA), collagen-1, and fibronectin. TGF-β1treatment 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-β1on ROS production and mitochondrial DNA damage and inhibited TGF-β1-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.
Department of Surgery, Biological Sciences Division, University of Chicago, Chicago, Illinois.
Samik
S
Bindu
Department of Surgery, Biological Sciences Division, University of Chicago, Chicago, Illinois.
Vinodkumar B
VB
Pillai
Department of Surgery, Biological Sciences Division, University of Chicago, Chicago, Illinois.
Abhinav
A
Kanwal
Department of Surgery, Biological Sciences Division, University of Chicago, Chicago, Illinois.
Sadhana
S
Samant
Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, Illinois; and.
Gökhan M
GM
Mutlu
Gladstone Institute, University of California, San Francisco, San Francisco, California.
Eric
E
Verdin
Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, Illinois; and.
Nickolai
N
Dulin
Department of Surgery, Biological Sciences Division, University of Chicago, Chicago, Illinois; mgupta@surgery.bsd.uchicago.edu.
Mahesh P
MP
Gupta
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin; D002454:Cell Differentiation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D018345:Mice, Knockout; D008954:Models, Biological; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D015415:Biomarkers; D024042:Collagen Type I; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D056566:Sirtuin 3; D003849:Deoxyguanosine
DNA damage; SIRT3; fibroblasts; pulmonary fibrosis