title: Sirtuin 3 Deregulation Promotes Pulmonary Fibrosis.
abstract: Oxidative stress leads to alveolar epithelial cell injury and fibroblast-myofibroblast differentiation (FMD), key events in the pathobiology of pulmonary fibrosis (PF). Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase regulator of antioxidant response and mitochondrial homeostasis. Here, we demonstrate reduced SIRT3 expression in the lungs of old mice compared to young mice, as well as in two murine models of PF. The analysis of the pattern of SIRT3 expression in the lungs of patients with PF revealed low SIRT3 staining within the fibrotic regions. We also demonstrated, using murine models of PF and human lung fibroblasts, that reduced SIRT3 expression in response to transforming growth factor beta 1 (TGFβ1) promotes acetylation (inactivation) of major oxidative stress response regulators, such as SOD2 and isocitrate dehydrogenase 2. Reduction of SIRT3 in human lung fibroblasts promoted FMD. By contrast, overexpression of SIRT3 attenuated TGFβ1-mediated FMD and significantly reduced the levels of SMAD family member 3 (SMAD3). Resveratrol induced SIRT3 expression and ameliorated acetylation changes induced by TGFβ1. We demonstrated that SIRT3-deficient mice are more susceptible to PF compared to control mice, and concomitantly exhibit enhanced SMAD3 expression. Collectively, these data define a SIRT3/TGFβ1 interaction during aging that may play a significant role in the pathobiology of PF.
authors: Division of Pulmonary Diseases, Critical Care and Environmental Medicine, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors: Meredith L
authors: ML
authors: Sosulski
authors: Division of Pulmonary Diseases, Critical Care and Environmental Medicine, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors: Rafael
authors: R
authors: Gongora
authors: Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston.
authors: Carol
authors: C
authors: Feghali-Bostwick
authors: Division of Pulmonary Diseases, Critical Care and Environmental Medicine, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors: Joseph A
authors: JA
authors: Lasky
authors: Division of Pulmonary Diseases, Critical Care and Environmental Medicine, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors: Cecilia G
authors: CG
authors: Sanchez
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D011658:Pulmonary Fibrosis / Q000473:pathology*; D000077185:Resveratrol; D056566:Sirtuin 3 / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D051900:Smad3 Protein; D013267:Stilbenes; D053773:Transforming Growth Factor beta1; D007521:Isocitrate Dehydrogenase; C000599591:isocitrate dehydrogenase 2, mouse; D013482:Superoxide Dismutase; D056566:Sirtuin 3; D000077185:Resveratrol
keywords: Age-related pathology; Lungs/pulmonary; Mitochondria; Reactive oxygen species; SIRT3