Pseudoexfoliation syndrome and aneurysms of the abdominal aorta

doi:10.1016/S0140-6736(00)03645-X

The Lancet

Volume 357, Issue 9253, 3 February 2001, Pages 359-360

https://doi.org/10.1016/S0140-6736(00)03645-X Get rights and content

Summary

We assessed the association between pseudoexfoliation syndrome, a common age-related fibrillopathy of unknown cause, and vascular diseases, especially aneurysms of the abdominal aorta. In a prospective single-blind study we ophthalmoscopically examined 55 patients with aneurysms of the abdominal aorta and 41 controls with carotic-artery occlusion. 24 of 55 patients with aortic aneurysm showed signs of manifest (17 of 55 patients) or early-stage (seven of 55) pseudoexfoliation syndrome. Eight of 41 control patients showed manifest (seven of 41 patients) and early (one of 41) ocular pseudoexfoliation (p=0·016). These findings, including histopathological examinations, suggest an association between aneurysms of the abdominal aorta and pseudoexfoliation syndrome.

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Cited by (171)

Differential Lysyl oxidase like 1 expression in pseudoexfoliation glaucoma is orchestrated via DNA methylation
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Pseudoexfoliation syndrome (PXF) is the most common cause of secondary open angle glaucoma worldwide. Single nucleotide polymorphisms (SNPs) in the gene Lysyl oxidase like 1 (LOXL1) are strongly associated with the development of pseudoexfoliation glaucoma (PXFG). However, these SNPs are also present in 50–80% of the general population, suggestive of other factors being involved in the pathogenesis of PXFG. In this study, we aimed to investigate the influence of epigenetic regulation, specifically DNA methylation, on LOXL1 expression in PXFG using human tenons fibroblasts (HTFs), aqueous humour and serum samples from donors with and without PXFG. LOXL1 expression in HTFs was measured by qPCR and Western Blotting and LOXL1 concentration in aqueous humour was determined by ELISA. Global DNA methylation levels were quantified using an ELISA for 5-methylcytosine. MeDIP assays assessed the methylation status of the LOXL1 promoter region. Expression of methylation-associated enzymes (DNMT1, DNMT3a and MeCP2) were determined by qPCR and inhibited by 0.3 μM 5-azacytidine (5-aza). Results showed that LOXL1 expression was significantly decreased in PXFG HTFs compared with Control HTFs at gene (Fold change 0.37 ± 0.05, P < 0.01) level and showed a decrease, when measured at the protein level (Fold change 0.65 ± 0.42, P = 0.22), however this was not found to be significant. LOXL1 concentration was increased in the aqueous of PXFG patients compared with Controls (2.76 ± 0.78 vs. 1.79 ± 0.33 ng/ml, P < 0.01). Increased global methylation (56.07% ± 4.87% vs. 32.39% ± 4.29%, P < 0.01) was observed in PXFG HTFs compared with Control HTFs, as was expression of methylation-associated enzymes (DNMT1 1.58 ± 0.30, P < 0.05, DNMT3a 1.89 ± 0.24, P < 0.05, MeCP2 1.63 ± 0.30, P < 0.01). Methylation-associated enzymes were also increased when measured at protein level (DNMT1 5.70 ± 2.64, P = 0.04, DNMT3a 1.79 ± 1.55, P = 0.42, MeCP2 1.64 ± 1.33, P = 0.45). LOXL1 promoter methylation was increased in patients with PXFG compared to Control patients in both blood (3.98 ± 2.24, 2.10 ± 1.29, P < 0.05) and HTF cells (37.31 ± 22.0, 8.66 ± 10.40, P < 0.01). Treatment of PXFG HTFs with in 5-azacytidine increased LOXL1 expression when compared with untreated PXFG HTFs (Fold change 2.26 ± 0.67, P < 0.05). These data demonstrate that LOXL1 expression is altered in PXFG via DNA methylation and that reversal of these epigenetic changes may represent future potential therapeutic targets in the management of PXFG.
Lysyl Oxidase Like 1: Biological roles and regulation
2020, Experimental Eye Research
Citation Excerpt :
PXF is also associated with abdominal aortic aneurysms (Djordjevic-Jocic et al., 2012; Gonen et al., 2013; Schumacher et al., 2001) and sensorineural hearing loss (Samarai et al., 2012). Aortic wall specimens from PXF patients and animal models (Behmoaras et al., 2008; Remus et al., 2012) showed significantly reduced expression levels of LOXL1 compared with controls and the elastic lamellae in the vessel walls were compromised (Schumacher et al., 2001). PXF patients also have significantly lower ankle branchial indexes compared with controls (Praveen et al., 2011) which may result from their elastotic vascular dysfunction.
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.
Risk Factors for Choroidal Detachment After Ahmed Valve Implantation in Glaucoma Patients
2020, American Journal of Ophthalmology
To assess the incidence and risk factors related to choroidal detachment after glaucoma drainage device (Ahmed valve) implantation.
Retrospective case-control study.
A total of 188 eyes of 188 glaucoma patients were enrolled who underwent Ahmed valve implantation surgery. Patients were divided into 2 groups according to the presence or absence of choroidal detachment. The data were analyzed for factors associated with choroidal detachment. Separately, we divided eyes with choroidal detachment into 2 subgroups according to severity and conducted a subanalysis. In addition, we also analyzed the factors associated with chamber collapse.
The incidence of choroidal detachment was 35.1% according to wide-field fundus photography and 16.9% according to 45-degree fundus photography. The current study showed that age, central corneal thickness, axial length, etiology of glaucoma, history of cataract or glaucoma, hypertension, diabetes, and severity of the visual field (MD) were different between the choroidal detachment and nonchoroidal detachment groups. A multivariate analysis showed significant differences in age (P = .035), etiology of glaucoma (pseudoexfoliation; PEX) (P = .028), lens status (pseudophakia) (P = .011), and hypertension (P = .011). The greater the intraocular pressure difference before and after surgery, the greater the size of the choroidal detachment. Chamber collapse risk was associated with only short axial length.
The detection of choroidal detachment after Ahmed valve implantation can be increased according to the introduction of wide fundus photography. The risk of choroidal detachment is associated with the etiology of glaucoma (PEX), older age, pseudophakia (lens status), and hypertension.
The role of lysyl oxidase-like 1 (LOXL1) in exfoliation syndrome and glaucoma
2019, Experimental Eye Research
Citation Excerpt :
Using a robust medical dataset, the Utah Population Database, XFS has been shown to be associated with pelvic organ prolapse (Wirostko et al., 2016), inguinal hernias (Besch et al., 2018), and chronic obstructive pulmonary disease (Wirostko et al., 2018). XFS has been also associated with cardiovascular diseases, including arterial hypertension, arrhythmia, cardiomyopathy, coronary artery disease, and particularly with aneurysms of the abdominal aorta, a potentially life-threatening complication (Schumacher et al., 2001; French et al., 2012; Katsi et al., 2013). Aortic wall specimens derived from XFS patients showed significantly reduced expression levels of LOXL1 compared with control specimens (Pasutto et al., 2017).
Exfoliation syndrome (XFS) is an age-related systemic disease that affects the extracellular matrix. It increases the risk of glaucoma (exfoliation glaucoma, XFG) and susceptibility to diseases of elastin-rich connective tissues. LOXL1 (lysyl oxidase-like 1) is still recognized as the major genetic effect locus in XFS and XFG in all populations worldwide, although its genetic architecture is incompletely understood. LOXL1 is a key cross-linking enzyme in elastic fiber formation and remodeling, which is compatible with the pathogenetic concept of XFS as a specific type of elastosis. This review provides an overview on the current knowledge about the role of LOXL1 in the etiology and pathophysiology of XFS and XFG. It covers the known genetic associations at the LOXL1 locus, potential mechanisms of gene regulation, implications of LOXL1 in XFS-associated fibrosis and connective tissue homeostasis, its role in the development of glaucoma and associated systemic diseases, and the currently available LOXL1-based in vivo and in vitro models. Finally, it also identifies gaps in knowledge and suggests potential areas for future research.
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2024, Journal of Clinical Medicine
Platelet Proteome Reveals Novel Targets for Hypercoagulation in Pseudoexfoliation Syndrome
2024, International Journal of Molecular Sciences

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Research LettersPseudoexfoliation syndrome and aneurysms of the abdominal aorta

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Ophthalmology

Am J Ophthalmol

Research Letters
Pseudoexfoliation syndrome and aneurysms of the abdominal aorta