HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 31, 22414-22425, August 3, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/31/22414    most recent M702321200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, Z. Articles by Campochiaro, P. A. Search for Related Content PubMed PubMed Citation Articles by Wu, Z. Articles by Campochiaro, P. A. Social Bookmarking                      What's this?

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

From the Departments of Ophthalmology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277

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 H₂O₂-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.

Received for publication, March 16, 2007 , and in revised form, May 18, 2007.

^* This work was supported by NEI, National Institutes of Health Grants EY05951 and Core Grants P30EY1765 and P30EY0572, a senior scientist award from Research to Prevent Blindness, New York, and by Dr. and Mrs. William Lake and Mr. and Mrs. Richard Heffner. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A George S. and Dolores Dore Eccles Professor of Ophthalmology. To whom correspondence should be addressed: Maumenee 719, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287-9277. Tel.: 410-955-5106; Fax: 410-614-9315; E-mail: pcampo{at}jhmi.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. Deleon, M. Lederman, E. Berenstein, T. Meir, M. Chevion, and I. Chowers Alteration in Iron Metabolism during Retinal Degeneration in rd10 Mouse Invest. Ophthalmol. Vis. Sci., March 1, 2009; 50(3): 1360 - 1365. [Abstract] [Full Text] [PDF]

				J. Zhou, S. R. Kim, B. S. Westlund, and J. R. Sparrow Complement Activation by Bisretinoid Constituents of RPE Lipofuscin Invest. Ophthalmol. Vis. Sci., March 1, 2009; 50(3): 1392 - 1399. [Abstract] [Full Text] [PDF]

				J. Wang, K. Ohno-Matsui, T. Yoshida, A. Kojima, N. Shimada, K.-i. Nakahama, O. Safranova, N. Iwata, T. C. Saido, M. Mochizuki, et al. Altered Function of Factor I Caused by Amyloid {beta}: Implication for Pathogenesis of Age-Related Macular Degeneration from Drusen J. Immunol., July 1, 2008; 181(1): 712 - 720. [Abstract] [Full Text] [PDF]

				L. Wang, Y. Chen, P. Sternberg, and J. Cai Essential Roles of the PI3 Kinase/Akt Pathway in Regulating Nrf2-Dependent Antioxidant Functions in the RPE Invest. Ophthalmol. Vis. Sci., April 1, 2008; 49(4): 1671 - 1678. [Abstract] [Full Text] [PDF]

				M. You, X. Liang, J. M. Ajmo, and G. C. Ness Involvement of mammalian sirtuin 1 in the action of ethanol in the liver Am J Physiol Gastrointest Liver Physiol, April 1, 2008; 294(4): G892 - G898. [Abstract] [Full Text] [PDF]