H2O2 accumulation by catalase reduction changes MAP kinase signaling in aged human skin in vivo

Department of Dermatology, Laboratory of Cutaneous Agining Research, Clinical Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Journal of Investigative Dermatology (Impact Factor: 6.37). 09/2005; 125(2):221-9. DOI: 10.1111/j.0022-202X.2005.23823.x
Source: PubMed

ABSTRACT To understand the molecular alterations occurring during the aging process, we compared mitogen-activated protein (MAP) kinase activities in the intrinsically aged and photoaged skins in the same individuals. Furthermore, we investigated the molecular events related to MAP kinase changes in intrinsically aged and photoaged skins. We found that extracellular-signal-regulated kinase (ERK) activity in photoaged skin was reduced, and that the activities of c-Jun N-terminal kinase (JNK) and p38 kinase were increased compared with intrinsically aged skin in the same individuals. Phospho-c-Jun levels and activator protein 1 activities in photoaged skin were also higher than in intrinsically aged skin. Moreover, catalase activity was found to be much reduced in primary dermal fibroblasts from photoaged skin, and as a result, H2O2 accumulated more in primary dermal fibroblasts in photoaged skin. In addition, treating primary dermal fibroblasts from photoaged skin with catalase reduced H2O2 levels, reversed aging-dependent MAP kinase changes, and inhibited matrix metalloproteinase (MMP)-1 expression. Our results indicate that the accumulation of reactive oxygen species due to catalase attenuation may be a critical aspect of the MAP kinase signaling changes that may lead to skin aging and photoaging in human skin in vivo. Thus, the induction and regulation of endogenous antioxidant enzymes including catalase may offer a strategy for preventing and treating skin aging.

Download full-text


Available from: Gi-Eun Rhie, Nov 21, 2014
  • Source
    • "In human skin, AP-1 activity is limited by the low level of c-Jun, whereas c-Fos is constitutively expressed (Fisher et al., 2000). We and others previously reported that stress-activated MAP Kinase pathways and c-Jun mRNA and protein are increased in aged, compared with young human skin in vivo (Chung et al., 2000; Shin et al., 2005; Fisher et al., 2009). These data suggest that reduced cellular spreading/mechanical force induces c-Jun, which in turn elevates MMP-1 expression in aged human skin. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The dermal compartment of human skin is largely composed of dense collagen-rich fibrils, which provide structural and mechanical support. Skin dermal fibroblasts, the major collagen-producing cells, are interact with collagen fibrils to maintain cell spreading and mechanical force for function. A characteristic feature of aged human skin is fragmentation of collagen fibrils, which is initiated by matrix metalloproteinase 1 (MMP-1). Fragmentation impairs fibroblast attachment and thereby reduces spreading. Here, we investigated the relationship among fibroblast spreading, mechanical force, MMP-1 expression, and collagen fibril fragmentation. Reduced fibroblast spreading due to cytoskeletal disruption was associated with reduced cellular mechanical force, as determined by atomic force microscopy. These reductions substantially induced MMP-1 expression, which led to collagen fibril fragmentation and disorganization in three-dimensional collagen lattices. Constraining fibroblast size by culturing on slides coated with collagen micropatterns also significantly induced MMP-1 expression. Reduced spreading/mechanical force induced transcription factor c-Jun and its binding to a canonical AP-1 binding site in the MMP-1 proximal promoter. Blocking c-Jun function with dominant negative mutant c-Jun significantly reduced induction of MMP-1 expression in response to reduced spreading/mechanical force. Furthermore, restoration of fibroblast spreading/mechanical force led to decline of c-Jun and MMP-1 levels and eliminated collagen fibril fragmentation and disorganization. These data reveal a novel mechanism by which alteration of fibroblast shape/mechanical force regulates c-Jun/AP-1-dependent expression of MMP-1 and consequent collagen fibril fragmentation. This mechanism provides a foundation for understanding the cellular and molecular basis of age-related collagen fragmentation in human skin.
    Aging cell 09/2014; 13(6). DOI:10.1111/acel.12265 · 5.94 Impact Factor
  • Source
    • "ROS have been acknowledged as controlling signal transduction through the activation of MAPK to transcription factors (Maziere et al., 2003). A previous study reported that the balance between the ERK activity and the JNK and p38 kinase activities shifted in favor of reduced cell growth and increased stress response in aged human skin (Shin et al., 2005). We showed that the ERK pathway remained activated after PDT, like ROS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Photodynamic therapy (PDT) is known to be effective in the photorejuvenation of photoaged skin. However, the molecular mechanisms of rejuvenation by PDT remain elusive. In this study we aimed to understand the molecular events occurring during the photorejuvenation after PDT in dermal fibroblasts in vitro. First, we found that PDT conditions resulted in an increased fibroblasts proliferation and motility in vitro. Under this condition, cells had increased intracellular reactive oxygen species (ROS) production. Importantly, PDT induced a prolonged activation of extracellular-signal-regulated kinase (ERK) with a corresponding increase in matrix metalloproteinase (MMP)-3 and collagen type Iα mRNA and protein. Moreover, inhibition of PDT-induced ERK activation significantly suppressed fibroblast proliferation and expression of MMP-3 and collagen type Iα following PDT. In addition, NAC (an antioxidant) inhibited PDT-induced fibroblast proliferation and ERK activation indicating that prolonged ERK activation and intracellular ROS contribute to the proliferation of fibroblasts and the dermal remodeling process for skin rejuvenation. We also identified increased collagen volume and decreased elastotic materials which are used as markers of photoaging in human skin samples using histochemistry. Results from this study suggest that intracellular ROS stimulated by PDT in dermal fibroblasts lead to prolonged activation of ERK, and eventually fibroblast proliferation and activation. Our data thus reveal a molecular mechanism underlying the skin rejuvenation effect of PDT.Journal of Investigative Dermatology accepted article preview online, 21 January 2013; doi:10.1038/jid.2013.25.
    Journal of Investigative Dermatology 01/2013; 133(9). DOI:10.1038/jid.2013.25 · 6.37 Impact Factor
  • Source
    • "Increased ROS concentration occurs in senescent fibroblast in vitro and in vivo (Scharffetter-Kochanek et al., 1997; Allen et al., 1999; Hutter et al., 2002; Shin et al., 2005). Fibroblasts constitute the principal component of the connective tissue. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. Its role in aging of the connective tissue has not yet been established, even though the incidence of aging-related disorders in connective tissue-rich organs is high, causing major disability in the elderly. We have now addressed this question experimentally by creating mice with conditional deficiency of the mitochondrial manganese superoxide dismutase in fibroblasts and other mesenchyme-derived cells of connective tissues in all organs. Here, we have shown for the first time that the connective tissue-specific lack of superoxide anion detoxification in the mitochondria results in reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis and muscle degeneration in mutant mice. Increase in p16(INK4a) , a robust in vivo marker for fibroblast aging, may contribute to the observed phenotype. This novel model is particularly suited to decipher the underlying mechanisms and to develop hopefully novel connective tissue-specific anti-aging strategies.
    Aging cell 11/2010; 10(2):239-54. DOI:10.1111/j.1474-9726.2010.00658.x · 5.94 Impact Factor
Show more