Oxidative exposure impairs TGF-β pathway via reduction of type II receptor and SMAD3 in human skin fibroblasts
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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.
KeywordsConnective tissue Oxidative stress Signal transduction Extracellular matrix Skin
We would like to thank Diane Fiolek for graphic material and administrative assistance; Dr. Maria Trojanowski (Boston University) for providing pCOL1α2-CAT; and Dr. Bert Vogelstein (Johns Hopkins) for providing 4X SBE-LUX. This work was supported, in part, by the National Institutes of Health, AG019364 (GF) and AG031452 (GF).
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