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

Abstract

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.

Diacron reactive oxygen metabolites and biological antioxidant potential tests for patients with age-related macular degeneration

“…Various diseases involve oxidative stress, including bronchial asthma, myocardial infarction, hypertension, diabetes, and hyperlipidemia [27,28]. Among the ocular diseases, there has been an accumulation of evidence demonstrating a significant relationship between oxidative stress and AMD, both in vitro and in vivo [10,29,30]. We previously demonstrated that MDA, an oxidative stress marker, is not only a marker of AMD, but is also a direct contributor to the pathogenesis of AMD [31].…”

“…nAMD is characterized by choroidal neovascularization (CNV) and an increase in intraretinal/subretinal fluid, which is strongly associated with the overexpression of vascular endothelial growth factor (VEGF). Multiple risk factors have been shown to contribute to the pathogenesis of nAMD, including obesity [4], hypertension [5], smoking [6], and light exposure [7,8]; it has been presumed that these act through inducing oxidative stress [9][10][11]. Previously, we showed that serum malondialdehyde (MDA), a marker of oxidative stress, was significantly higher in patients with nAMD than in those without AMD, and that there was a significant correlation between serum MDA levels and the area of CNV [12].…”

Diacron reactive oxygen metabolites and biological antioxidant potential tests for patients with age-related macular degeneration

“…27,28 Among the ocular diseases, there has been an accumulation of evidence demonstrating a significant relationship between oxidative stress and AMD, both in vitro and in vivo. [29][30][31] We previously demonstrated that MDA, an oxidative stress marker, is not only a marker of AMD, but is also a direct contributor to the pathogenesis of AMD. 32 In particular, we showed that serum MDA levels in patients with nAMD were significantly higher than in control subjects, and that there was a significant correlation between serum MDA levels and CNV area.…”

Autophagy and Age-Related Eye Diseases

“…However, whether AMD is a multifactorial progressive disease that results from both genetic and environmental insults. Chronic inflammation and oxidative stress are involved in it, although the exact mechanism of its pathogenesis is not fully clear [85][86][87][88]. Because high metabolic activity, abundant consumption of oxygen and high proportion of polyunsaturated fatty acids in RPE, RPE is more sensitive to oxidative stress damage [89].…”