SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis

• Type of Material: Article
• Authors: Kaname Akamata, Northwestern University; Jun Wei, Northwestern University; Mitra Bhattacharyya, Northwestern University; Paul Cheresh, Northwestern University; Michael Y. Bonner, Emory University; Jack Arbiser, Emory University; Kirtee Raparia, Northwestern University; Mahesh P. Gupta, University of Chicago; David W. Kamp, Northwestern University; John Varga, Northwestern University
• Language: English
• Date: 2016-10-25
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Akamata et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.12504
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 7
• Issue: 43
• Start Page: 69321
• End Page: 69336
• Grant/Funding Information: Supported by grants from the National Institutes of Health (AR-49025 to JV, HL-111455 and HL-117041 to MPG, NIH-ES020357 to DWK), National Scleroderma Foundation (JV) and VA Merit (DWK).
• Keywords: HONOKIOL; MITOCHONDRIAL-DNA; GROWTH-FACTOR-BETA; SIRT3; FIBROTIC RESPONSES; CANCER; PULMONARY-FIBROSIS; Cell Biology; MECHANISMS; SCLERODERMA; myofibroblast; Pathology Section; Science & Technology; SIRTUINS; fibrosis; Oncology; Life Sciences & Biomedicine; DEACETYLATES; TGF-beta; ROS
• Research Categories: Health Sciences, General; Health Sciences, Medicine and Surgery

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-β 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.