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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acetylcysteine / pharmacology
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Collagen Type I / metabolism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Free Radical Scavengers / pharmacology
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Gene Expression Regulation, Developmental*
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Humans
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / genetics*
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RNA, Messenger / genetics*
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / biosynthesis
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Receptors, Transforming Growth Factor beta / drug effects
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Receptors, Transforming Growth Factor beta / genetics*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Skin / cytology
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Skin / drug effects
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Skin / metabolism*
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Skin Aging / drug effects
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Skin Aging / genetics*
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Smad3 Protein / biosynthesis
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Smad3 Protein / drug effects
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Smad3 Protein / genetics*
Substances
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Collagen Type I
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Free Radical Scavengers
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RNA, Messenger
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Receptors, Transforming Growth Factor beta
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SMAD3 protein, human
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Smad3 Protein
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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Acetylcysteine