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: 7.22). 09/2005; 125(2):221-9. DOI: 10.1111/j.0022-202X.2005.23823.x
Source: PubMed


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.

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Available from: Gi-Eun Rhie, Nov 21, 2014
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    • "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. "
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    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.
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    • "However, the excessive ROS generation induced by PUVA overwhelmed the cell redox system. Because antioxidant enzymes are themselves targets of oxidative modifications [60], PUVA-SIPS mimics the alterations observed in photoaged cells [61]. In particular, PUVA-treated HDFs showed a dramatic decline in Cat activity and a significant reduction in intracellular GSH, which are both critical for preserving cellular redox balances, with a very low recovery to basal values. "
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    • "Previous studies reported that photooxidative stress is possibly involved in MMP-1 regulation in skin cells including keratinocytes [13, 14], and improving antioxidant defense system may thus be mechanisms underlying the photoprotective effects of phytochemicals ubiquitously present in medicinal plants. ROS accumulation in photoaged skins has been suggested to associate with increased MMP-1 expression, which could be reversed by promoting capacity of antioxidant defenses including catalase [15], GSH, and GPx [10, 16]. They are essential endogenous antioxidant defenses controlling redox balance accountable for protection against photooxidative stress in the keratinocytes and skin carcinogenesis [17, 18], and redox regulation of MMP-1 might, therefore, represent a strategy for photoaging prevention. "
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