Mechanism of UV Induced ROS Generation: NADPH Oxidase Activation

The primary mechanism of UV induced skin aging is the production and generation of reactive oxygen species (ROS). ROS/free radicals is one of the main causes of chronologic and photo skin aging . ROS exerts aging effect via damaging and oxidizing biomacromolecules and cellular components. ROS also are intracellular signals which activate and regulate transcriptions factors and genes involved in the molecular mechanism of the aging process. One mechanism of UV induced ROS generation is via NADPH oxidase activation. NADPH oxidase (NOX) is an enzyme that catalyzes the production of superoxide from oxygen and NADPH. The superoxide produced is quantitatively converted to hydrogen peroxide which in turn can be further converted to other ROS. Several oxidoreductases have been identified to generate superoxide. These include cyclooxygenase, cytochrome P450 enzymes, nitric-oxide synthase, mitochondrial NADH:ubiquinone oxidoreductase, and NADPH oxidase. Differ from the other oxidoreductases that produce superoxide, NADPH oxidase only catalyzes the production of superoxide from oxygen and NADPH. Whereas the other enzymes produce ROS only as byproducts along with their specific catalytic pathways at mitochondria aerobic oxygen metabolism or from other sources. There are seven isoforms of NOX being identified thus far. Different isoforms of NADPH oxidase seems to be tissue or cell type specific. The NADPH oxidase paradigm was largely derived from studies in immune cells such as neutrophils and macrophages.

Skin also contain NADPH oxidase subunits. UV-induced NADPH oxidase activity has been studied in skin keratinocytes in vitro. NADPH oxidase activity is induced following UV exposure. In keratinocytes, NADPH oxidase activity is induced 2-fold within 20 minutes following UV exposure. Block of NADPH oxidase activity using small interfering RNA (siRNA) and/or inhibitor of NADPH oxidase completely blocked UV-induced hydrogen peroxide generation, indicating that UV induced ROS produced by mitochondria or other sources are due to NADPH oxidase activation. Thus, NADPH oxidase is a major enzymatic source of hydrogen peroxide production following UV irradiation in keratinocytes.

Many stress stimuli can acutely activate NOX enzyme activity before the transcriptional and/or post transcriptional activation of NOX genes. The mechanism for activation of NOX is mediated by an increase in intracellular calcium concentration and protein kinase C (PKC) mediated phosphorylation. NOX phosphorylation by PKC is essential for NADPH oxidase activation. As with PKC, increased intracellular Ca2+ has been observed in cells exposed to various stress. The binding of calcium to the NOX calcium binding domain also activates NADPH oxidase and this mechanism of UV induced NADPH oxidase activation was observed in skin keratinocytes. An increase in intracellular Ca2+ can be a secondary response after PKC activation and vice versa. Activation of conventional PKC isoforms α, β, and γ is Ca2+-dependent; thus, Ca2+ influx and PKC activation is inter-related. NADPH oxidase-generated ROS may further increase intracellular Ca2+ by enhancing the membrane ion channel activity and/or Ca2+ release from intracellular stores. NADPH oxidase gene may also be activated subsequently via yet unclear signal tranduction pathway/mechanism. AP-1 – a transcription factor activated by ROS signal which regulate a number of genes (e.g matrix metalloproteinase) in aging process – binding sequence has been identified in some NOX isoforms, suggesting AP-1 signaling may regulate and increase NADPH oxidase.

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