Oxidative Stress Modulates Complement Factor H Expression in Retinal Pigmented Epithelial Cells by Acetylation of FOXO3

Abstract

Age-related macular degeneration (AMD), the leading cause of severe vision loss in the elderly, is a complex disease that results from genetic modifications that increase susceptibility to environmental exposures. Smoking, a major source of oxidative stress, increases the incidence and severity of AMD, and antioxidants slow progression, suggesting that oxidative stress plays a major role. Polymorphisms in the complement factor H (CFH) gene that reduce activity of CFH increase the risk of AMD. In this study we demonstrate an interaction between these two risk factors, because oxidative stress reduces the ability of an inflammatory cytokine, interferon-␥, to increase CFH expression in retinal pigmented epithelial cells. The interferon-␥-induced increase in CFH is mediated by transcriptional activation by STAT1, and its suppression by oxidative stress is mediated by acetylation of FOXO3, which enhances FOXO3 binding to the CFH promoter, reduces its binding to STAT1, inhibits STAT1 interaction with the CFH promoter, and reduces expression of CFH. Expression of SIRT1, a mammalian homolog of NAD-dependent protein deacetylase sir2, attenuated FOXO3 recruitment to the CFH regulatory region and reversed the H 2 O 2 -induced repression of CFH gene expression. These data suggest an important interaction between environmental exposure and genetic susceptibility in the pathogenesis of AMD and, by elucidating molecular signaling involved in the interaction, provide potential targets for therapeutic intervention.

Involvement of mammalian sirtuin 1 in the action of ethanol in the liver

“…Recent evidence suggests that oxidative stress downregulates SIRT1 (8,33,34). It is tempting to postulate that the ongoing reactive oxygen species generation by ethanol metabolism could prolong the suppression of SIRT1 activity in the liver.…”

Essential Role of Surface-Bound Complement Factor H in Controlling Immune Complex–Induced Arthritis

“…Synovial cells are now stressed and susceptible to complement-induced injury, further increasing the requirement for fH control of AP activation. Notably, this same role for fH in regulation of inflammation is observed in ischemic injury in renal tubular epithelial cells (41) and in oxidative stress in retinal pigmented epithelial cells (42) fH is increasingly recognized as a centrally important protein in the regulation and control of AP activation on multiple tissue sites. The normal concentration of fH in plasma ranges from 233 to 269 mg/ml in young and old individuals, respectively (43), although other studies suggest that the concentration of fH in plasma is 2-fold higher (44,45).…”

The critical role of adrenomedullin and its binding protein, AMBP-1, in neuroprotection

“…However, in certain CNS pathologies such as multiple sclerosis (Ingram et al , 2010 ), there is a reported increase in AMBP-1 levels. Infl ammatory cytokines, particularly IFN-γ , have been recognized as positive regulators of AMBP-1 expression (Wu et al , 2007b ), whereas Cerebral ischemia results in infl ammation and production of reactive oxygen species. Reactive oxygen species (ROS) causes acetylation (Ac) of FOXO3, which translocates into the nucleus and binds to the AMBP-1 promoter, followed by suppression of AMBP-1 expression.…”

“…The balance between negative and positive regulators will determine whether AMBP-1 level in brain disease is up-or down-regulated. Wu et al (2007b) demonstrated that during infl ammation, IFN-γ stimulates the nuclear translocation of STAT1 together with relatively small amount of FOXO3 to bind to the STAT1 response element in the AMBP-1 promoter region, leading to up-regulation of AMBP-1 expression. However, in the presence of reactive oxygen species, FOXO3 undergoes a conformational change by acetylation.…”