title: Oxidative exposure impairs TGF-β pathway via reduction of type II receptor and SMAD3 in human skin fibroblasts.
abstract: Exposure to oxidants results in cellular alterations that are implicated in aging and age-associated diseases. Here, we report that brief, low-level oxidative exposure leads to long-term elevation of cellular reactive oxygen species (ROS) levels and oxidative damage in human skin fibroblasts. Elevated ROS impairs the transforming growth factor-β (TGF-β) pathway, through reduction of type II TGF-β receptor (TβRII) and SMAD3 protein levels. This impairment results in reduced expression of connective tissue growth factor (CTGF/CCN2) and type I collagen, which are regulated by TGF-β. Restoration of TβRII and SMAD3 together, but not separately, reinstates TGF-β signaling and increases CTGF/CCN2 and type I collagen levels. Treatment with the anti-oxidant N-acetylcysteine reduces ROS elevation and normalizes TGF-β signaling and target gene expression. These data reveal a novel linkage between limited oxidant exposure and altered cellular redox homeostasis that results in impairment of TGF-β signaling. This linkage provides new insights regarding the mechanism by which aberrant redox homeostasis is coupled to decline of collagen production, a hallmark of human skin aging.
authors.affiliation: Department of Dermatology, Medical School, University of Michigan, 1301 E Catherine, Rm 6447 Med Sci I, Ann Arbor, MI, 48109-5609, USA.
authors.forename: Tianyuan
authors.initials: T
authors.lastname: He
authors.forename: Taihao
authors.initials: T
authors.lastname: Quan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shao
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D024042:Collagen Type I / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015595:Skin Aging / Q000187:drug effects / Q000235:genetics*; D051900:Smad3 Protein / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D016166:Free Radical Scavengers; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D000111:Acetylcysteine