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Oxidative exposure impairs TGF-β pathway via reduction of type II receptor and SMAD3 in human skin fibroblasts

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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.

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Acknowledgments

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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Authors and Affiliations

  1. Department of Dermatology, Medical School, University of Michigan, 1301 E Catherine, Rm 6447 Med Sci I, Ann Arbor, MI, 48109-5609, USA

    Tianyuan He, Taihao Quan, Yuan Shao, John J. Voorhees & Gary J. Fisher

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  1. Tianyuan He
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  2. Taihao Quan
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  3. Yuan Shao
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Correspondence to Gary J. Fisher.

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He, T., Quan, T., Shao, Y. et al. Oxidative exposure impairs TGF-β pathway via reduction of type II receptor and SMAD3 in human skin fibroblasts. AGE 36, 9623 (2014). https://doi.org/10.1007/s11357-014-9623-6

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