Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis

Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced A...

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Main Authors:	Du, Hongjun, Xiao, Xu, Stiles, Travis, Douglas, Christopher, Ho, Daisy, Shaw, Peter X.
Format:	Online
Language:	English
Published:	2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035113/

id	pubmed-5035113
recordtype	oai_dc
spelling	pubmed-50351132016-09-23 Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis Du, Hongjun Xiao, Xu Stiles, Travis Douglas, Christopher Ho, Daisy Shaw, Peter X. Article Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced AMD, geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD) and result in the loss of central vision. The exact mechanism for developing early AMD and progressing to advanced stage of disease is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as the cause of AMD progression. Together, complement factor H (CFH) and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress from activities such as smoking has also demonstrated a powerful contribution to AMD progression. To extend our previous finding that genetic polymorphisms in CFH results in OxPLs and the risk-form of CFH (CFH Y402H) has reduced affinity for oxidized phospholipids, and subsequent diminished capacity which subsequently diminishes the capability to attenuate the inflammatory effects of these molecules, we compared the binding properties of CFH and CFH related protein 1 (CFHR1), which is also associated with disease risk, to OxPLs and their effects on modulating inflammation and lipids uptake. As both CFH-402H and CFHR1 are associated with increased risk to AMD, we hypothesized that like CFH-402H, CFHR1 contribution to AMD risk may also be due to its diminished affinity for OxPLs. Interestingly, we found that association of CFHR1 with OxPLs was not statistically different than CFH. However, binding of CFHR1 did not elicit the same protective benefits as CFH in that both inflammation and lipid uptake are unaffected by CFHR1 association with OxPLs. These findings demonstrate a novel and interesting complexity to the potential interplay between the complement system and oxidative stress byproducts, such as OxPLs, in the mechanistic contribution to AMD. Future work will aim to identify the molecular distinctions between CFH and CFHR1 which confer protection by the former, but not latter molecules. Understanding the molecular domains necessary for protection could provide interventional insights in the generation of novel therapeutics for AMD and other diseases associated with oxidative stress. 2016-02-26 2016-02 /pmc/articles/PMC5035113/ /pubmed/27668132 http://dx.doi.org/10.4236/ojoph.2016.61006 Text en http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Du, Hongjun Xiao, Xu Stiles, Travis Douglas, Christopher Ho, Daisy Shaw, Peter X.
spellingShingle	Du, Hongjun Xiao, Xu Stiles, Travis Douglas, Christopher Ho, Daisy Shaw, Peter X. Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis
author_facet	Du, Hongjun Xiao, Xu Stiles, Travis Douglas, Christopher Ho, Daisy Shaw, Peter X.
author_sort	Du, Hongjun
title	Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis
title_short	Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis
title_full	Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis
title_fullStr	Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis
title_full_unstemmed	Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis
title_sort	novel mechanistic interplay between products of oxidative stress and components of the complement system in amd pathogenesis
description	Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced AMD, geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD) and result in the loss of central vision. The exact mechanism for developing early AMD and progressing to advanced stage of disease is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as the cause of AMD progression. Together, complement factor H (CFH) and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress from activities such as smoking has also demonstrated a powerful contribution to AMD progression. To extend our previous finding that genetic polymorphisms in CFH results in OxPLs and the risk-form of CFH (CFH Y402H) has reduced affinity for oxidized phospholipids, and subsequent diminished capacity which subsequently diminishes the capability to attenuate the inflammatory effects of these molecules, we compared the binding properties of CFH and CFH related protein 1 (CFHR1), which is also associated with disease risk, to OxPLs and their effects on modulating inflammation and lipids uptake. As both CFH-402H and CFHR1 are associated with increased risk to AMD, we hypothesized that like CFH-402H, CFHR1 contribution to AMD risk may also be due to its diminished affinity for OxPLs. Interestingly, we found that association of CFHR1 with OxPLs was not statistically different than CFH. However, binding of CFHR1 did not elicit the same protective benefits as CFH in that both inflammation and lipid uptake are unaffected by CFHR1 association with OxPLs. These findings demonstrate a novel and interesting complexity to the potential interplay between the complement system and oxidative stress byproducts, such as OxPLs, in the mechanistic contribution to AMD. Future work will aim to identify the molecular distinctions between CFH and CFHR1 which confer protection by the former, but not latter molecules. Understanding the molecular domains necessary for protection could provide interventional insights in the generation of novel therapeutics for AMD and other diseases associated with oxidative stress.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035113/
_version_	1613659965591912448

Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis

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