title: SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis.
abstract: Constitutive fibroblast activation is responsible for organ fibrosis in fibrotic disorders including systemic sclerosis (SSc), but the underlying mechanisms are not fully understood, and effective therapies are lacking. We investigated the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and its modulation by hexafluoro, a novel fluorinated synthetic honokiol analogue, in the context of fibrosis. We find that augmenting cellular SIRT3 by forced expression in normal lung and skin fibroblasts, or by hexafluoro treatment, blocked intracellular TGF-ß signaling and fibrotic responses, and mitigated the activated phenotype of SSc fibroblasts. Moreover, hexafluoro attenuated mitochondrial and cytosolic reactive oxygen species (ROS) accumulation in TGF-β-treated fibroblasts. Remarkably, we found that the expression of SIRT3 was significantly reduced in SSc skin biopsies and explanted fibroblasts, and was suppressed by TGF-β treatment in normal fibroblasts. Moreover, tissue levels of acetylated MnSOD, a sensitive marker of reduced SIRT3 activity, were dramatically enhanced in lesional skin and lung biopsies from SSc patients. Mice treated with hexafluoro showed substantial attenuation of bleomycin-induced fibrosis in the lung and skin. Our findings reveal a cell-autonomous function for SIRT3 in modulating fibrotic responses, and demonstrate the ability of a novel pharmacological SIRT3 agonist to attenuate fibrosis in vitro and in vivo. In light of the impaired expression and activity of SIRT3 associated with organ fibrosis in SSc, pharmacological approaches for augmenting SIRT3 might have therapeutic potential.
authors.affiliation: Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Kaname
authors.initials: K
authors.lastname: Akamata
authors.affiliation: Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Mitra
authors.initials: M
authors.lastname: Bhattacharyya
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Cheresh
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Bonner
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA.|Atlanta Veterans Administration Medical Center and Winship Cancer, Atlanta, GA, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.affiliation: Department of Pathology, Northwestern University, Chicago, IL, USA.
authors.forename: Kirtee
authors.initials: K
authors.lastname: Raparia
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL, USA.
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Gupta
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Kamp
authors.affiliation: Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005355:Fibrosis / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D034622:RNA Interference; D012595:Scleroderma, Systemic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000201:enzymology* / Q000473:pathology
chemical_list: D006845:Hydrocarbons, Fluorinated; D001761:Bleomycin; D056566:Sirtuin 3
keywords: Pathology Section; ROS; SIRT3; TGF-β; fibrosis; myofibroblast