title: Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts.
abstract: Pulmonary fibrosis is a severe condition with no cure and limited therapeutic options. A better understanding of its pathophysiology is needed. Recent studies have suggested that pulmonary fibrosis may be driven by accelerated aging-related mechanisms. Sirtuins (SIRTs), particularly SIRT1, SIRT3, and SIRT6, are well-known mediators of aging; however, limited data exist on the contribution of sirtuins to lung fibrosis. We assessed the mRNA and protein levels of all seven known sirtuins in primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in comparison with lung fibroblasts from healthy controls. These unbiased tests revealed a tendency for all sirtuins to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7. Similarly, SIRT7 was decreased in lung tissues of bleomycin-challenged mice. Inhibition of SIRT7 with siRNA in cultured lung fibroblasts resulted in an increase in collagen and α-smooth muscle actin (α-SMA). Reciprocally, overexpression of SIRT7 resulted in lower basal and TGF-β-induced levels of COL1A1, COL1A2, COL3A1, and α-SMA mRNAs, as well as collagen and α-SMA proteins. Induced changes in SIRT7 had no effect on endogenous TGF-β mRNA levels or latent TGF-β activation, but overexpression of SIRT7 reduced the levels of Smad3 mRNA and protein. In conclusion, the decline in SIRT7 in lung fibroblasts has a profibrotic effect, which is mediated by changes in Smad3 levels.
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Maryland Health Care Center, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland; awyman@umm.edu.|Research Service, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland; and.|Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Wyman
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Zahid
authors.initials: Z
authors.lastname: Noor
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Rita
authors.initials: R
authors.lastname: Fishelevich
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Virginia
authors.initials: V
authors.lastname: Lockatell
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Nirav G
authors.initials: NG
authors.lastname: Shah
authors.affiliation: Research Service, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland; and.|Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Nevins W
authors.initials: NW
authors.lastname: Todd
authors.affiliation: Research Service, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland; and.|Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Sergei P
authors.initials: SP
authors.lastname: Atamas
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008168:Lung / Q000473:pathology*; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D012333:RNA, Messenger; C510661:SIRT7 protein, human; C539736:Sirt7 protein, mouse; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D003094:Collagen; D037761:Sirtuins
keywords: SIRT7; aging; idiopathic pulmonary fibrosis; pulmonary fibrosis; systemic sclerosis