Elevated homocysteine levels in aqueous humor of patients with pseudoexfoliation glaucoma

doi:10.1016/j.ajo.2004.02.027

American Journal of Ophthalmology

Volume 138, Issue 1, July 2004, Pages 162-164

https://doi.org/10.1016/j.ajo.2004.02.027 Get rights and content

Abstract

Purpose

To determine total homocysteine levels in aqueous humor of pseudoexfoliation open-angle glaucoma patients.

Design

Case-control study.

Methods

Total homocysteine levels were measured by enzyme-linked immunosorbent assay in aqueous humor and plasma of 29 patients with pseudoexfoliation glaucoma and 31 control patients with cataract. Patients with factors affecting homocysteine levels were excluded.

Results

We observed significantly elevated (twofold) homocysteine levels in the aqueous humor of the glaucoma patients (Z = −5.11, P < .0001). Additionally, the calculated ratio (plasma:aqueous humor) was significantly lower in these patients (Z = −3.57, P < .001), and aqueous homocysteine was significantly correlated with their respective elevated plasma levels (r = .42, P = .02).

Conclusions

Because homocysteine induces vascular injury and alterations of extracellular matrix, high aqueous homocysteine may trigger the abnormal matrix accumulation characteristic. It may reflect the proposed impairment of the blood-aqueous barrier of pseudoexfoliation open-angle glaucoma and be involved in its pathogenesis.

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The Desmosine content in the lens capsules were 3-fold and 6-fold elevated in PXF (P = 0.02) and PXF-G (P = 0.01) respectively compared to the cataract-alone, indicating increased elastin degradation. A significant increase in the transcript levels of the CLU, FBLN4, EMILIN1, FBLN5, FN1, FBN1, LOXL1 along with significant changes in protein expression of CLU, FBLN5, FBN1 and LOXL1 signified up-regulation of the elastogenesis machinery. The study provides direct evidence of augmented elastin degradation and turnover in the lens capsule of PXF marked by increased Desmosine content and the expression of proteins involved in mature elastin formation.
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Lysyl Oxidase Like 1 (LOXL1) is a gene that encodes for the LOXL1 enzyme. This enzyme is required for elastin biogenesis and collagen cross-linking, polymerising tropoelastin monomers into elastin polymers. Its main role is in elastin homeostasis and matrix remodelling during injury, fibrosis and cancer development. Because of its vast range of biological functions, abnormalities in LOXL1 underlie many disease processes. Decreased LOXL1 expression is observed in disorders of elastin such as Cutis Laxa and increased expression is reported in fibrotic disease such as Idiopathic Pulmonary Fibrosis. LOXL1 is also downregulated in the lamina cribrosa in pseudoexfoliation glaucoma and genetic variants in the LOXL1 gene have been linked with an increased risk of developing pseudoexfoliation glaucoma and pseudoexfoliation syndrome. However the two major risk alleles are reversed in certain ethnic groups and are present in a large proportion of the normal population, implying complex genetic and environmental regulation is involved in disease pathogenesis. It also appears that the non-coding variants in intron 1 of LOXL1 may be involved in the regulation of LOXL1 expression. Gene alteration may occur via a number of epigenetic and post translational mechanisms such as DNA methylation, long non-coding RNAs and microRNAs. These may represent future therapeutic targets for disease. Environmental factors such as hypoxia, oxidative stress and ultraviolet radiation exposure alter LOXL1 expression, and it is likely a combination of these genetic and environmental factors that influence disease development and progression. In this review, we discuss LOXL1 properties, biological roles and regulation in detail with a focus on pseudoexfoliation syndrome and glaucoma.
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Taken collectively, the data shown in Figs. 7 and 8 suggest that NRF2 plays an important role in Müller cell mitochondrial and glycolytic adaptive responses to Hhcy. Hhcy is implicated in several retinal degenerative diseases including glaucoma [1,3,6,63,64] and Hcy levels are elevated in plasma and tears of patients with some forms of the disease, especially XFS [65,66]. RGC loss is the defining cellular event underlying glaucoma, a disease with complex pathogenicity.
Hyperhomocysteinemia (Hhcy), or increased levels of the excitatory amino acid homocysteine (Hcy), is implicated in glaucoma, a disease characterized by increased oxidative stress and loss of retinal ganglion cells (RGCs). Whether Hhcy is causative or merely a biomarker for RGC loss in glaucoma is unknown. Here we analyzed the role of NRF2, a master regulator of the antioxidant response, in Hhcy-induced RGC death in vivo and in vitro. By crossing Nrf2^−/− mice and two mouse models of chronic Hhcy (Cbs^+/- and Mthfr^+/- mice), we generated Cbs^+/-Nrf2^−/− and Mthfr^+/-Nrf2^−/− mice and performed systematic analysis of retinal architecture and visual acuity followed by assessment of retinal morphometry and gliosis. We observed significant reduction of inner retinal layer thickness and reduced visual acuity in Hhcy mice lacking NRF2. These functional deficits were accompanied by fewer RGCs and increased gliosis. Given the key role of Müller glial cells in maintaining RGCs, we established an ex-vivo indirect co-culture system using primary RGCs and Müller cells. Hhcy-exposure decreased RGC viability, which was abrogated when cells were indirectly cultured with wildtype (WT) Müller cells, but not with Nrf2^−/− Müller cells. Exposure of WT Müller cells to Hhcy yielded a robust mitochondrial and glycolytic response, which was not observed in Nrf2^−/− Müller cells. Taken together, the in vivo and in vitro data suggest that deleterious effects of Hhcy on RGCs are likely dependent upon the health of retinal glial cells and the availability of an intact retinal antioxidant response mechanism.
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Brief reportElevated homocysteine levels in aqueous humor of patients with pseudoexfoliation glaucoma

Abstract

Purpose

Design

Methods

Results

Conclusions

Am J Ophthalmology

Trends Neurosci

Brief report
Elevated homocysteine levels in aqueous humor of patients with pseudoexfoliation glaucoma