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Integration of Miniaturized Solid Phase Extraction and LC-MS/MS Detection of 3-Nitrotyrosine in Human Urine for Clinical Applications
Published on: July 14, 2017
3-Nitrotyrosine as a biomarker for vascular involvement in Fabry disease
Dominique A Joly1, Jean-Pierre Grünfeld1
1Service de Nephrologie, Faculté de Médecine, Hôpital Necker-Enfants Malades, Université Paris-Descartes, Assistance Publique-Hôpitaux de Paris, Paris, France.
Insights
Enzyme replacement therapy for Fabry disease doesn't stop vascular issues. New research links glycosphingolipid buildup to oxidative stress, suggesting new therapeutic targets beyond current treatments.
Area of Science:
- Biochemistry
- Vascular Biology
- Genetic Disorders
Background:
- Enzyme replacement therapy (ERT) for Fabry disease began in 2001.
- Despite ERT, many patients experience ongoing vascular disease progression.
- The accumulation of glycosphingolipids in endothelial cells is a hallmark of Fabry disease.
Purpose of the Study:
- To investigate the mechanisms underlying persistent vascular disease in Fabry patients on ERT.
- To explore the relationship between glycosphingolipid accumulation and endothelial dysfunction.
- To identify potential biomarkers for Fabry vasculopathy and therapeutic targets.
Main Methods:
- Analysis of endothelial cell samples from Fabry disease patients.
- Measurement of globotriaosylceramide levels.
- Assessment of 3-nitrotyrosine formation as an indicator of oxidative stress and endothelial nitric oxide synthase (eNOS) uncoupling.
Main Results:
- A correlation was found between globotriaosylceramide accumulation in endothelial cells and increased 3-nitrotyrosine formation.
- This finding suggests a link between stored glycosphingolipids and eNOS uncoupling.
- 3-Nitrotyrosine serves as a potential marker for Fabry vasculopathy.
Conclusions:
- Endothelial glycosphingolipid accumulation contributes to vascular damage in Fabry disease, independent of ERT's primary mechanism.
- eNOS uncoupling, indicated by 3-nitrotyrosine, is a key feature of Fabry vasculopathy.
- Targeting oxidative stress pathways may offer novel therapeutic strategies for Fabry disease.
Abstract:
Enzyme replacement therapy in Fabry disease was initiated in 2001. In a significant proportion of patients, the apparent removal of stored glycosphingolipid from the endothelial cells does not prevent progression of vascular disease. Shu et al. show a link between accumulation of globotriaosylceramide in the endothelial cells and 3-nitrotyrosine formation, indicating endothelial nitric oxide synthase uncoupling. 3-Nitrotyrosine will be useful to better understand Fabry vasculopathy, and to evaluate additional therapeutic interventions targeting oxidative stress.
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