Related Experiment Video
Updated: Jul 2, 2026
Examining the Dynamics of Cellular Adhesion and Spreading of Epithelial Cells on Fibronectin During Oxidative Stress
Published on: October 13, 2019
Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease
Jin-Song Shen1, Xing-Li Meng, David F Moore
1Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
Insights
Globotriaosylceramide (Gb(3)) accumulation in Fabry disease causes oxidative stress and increases cell adhesion molecules in vascular endothelial cells. Reducing Gb(3) levels lessens these effects, offering therapeutic insights.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Fabry disease is an X-linked vasculopathy due to alpha-galactosidase A deficiency.
- This deficiency leads to globotriaosylceramide (Gb(3)) accumulation in cells.
- The precise role of Gb(3) in disease pathogenesis remains unclear.
Purpose of the Study:
- To investigate the hypothesis that Gb(3) accumulation in vascular endothelium contributes to oxidative stress and cell adhesion molecule expression.
- To explore the direct impact of Gb(3) on endothelial cells.
Main Methods:
- Loading cultured vascular endothelial cells with Gb(3).
- Measuring reactive oxygen species (ROS) production and cell adhesion molecule expression (ICAM-1, VCAM-1, E-selectin).
- Treating cells with inhibitors of glycosphingolipid synthase or alpha-galactosidase A to reduce Gb(3).
- Comparing ROS generation in endothelial cells exposed to plasma from Fabry patients versus controls.
Main Results:
- Gb(3) loading increased intracellular ROS production and adhesion molecule expression in a dose-dependent manner.
- Reducing endogenous Gb(3) decreased adhesion molecule expression.
- Fabry patient plasma significantly increased endothelial cell ROS generation, independent of intracellular Gb(3) levels.
Conclusions:
- Excess intracellular Gb(3) directly induces oxidative stress and up-regulates cell adhesion molecules in vascular endothelial cells.
- Plasma factors in Fabry disease may also contribute to endothelial oxidative stress.
Abstract:
Fabry disease, an X-linked systemic vasculopathy, is caused by a deficiency of alpha-galactosidase A resulting in globotriaosylceramide (Gb(3)) storage in cells. The pathogenic role of Gb(3) in the disease is not known. Based on previous work, we tested the hypothesis that accumulation of Gb(3) in the vascular endothelium of Fabry disease is associated with increased production of reactive oxygen species (ROS) and increased expression of cell adhesion molecules. Gb(3)-loading resulted in increased intracellular ROS production in cultured vascular endothelial cells in a dose-dependent manner. Increased Gb(3) also induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. Reduction of endogenous Gb(3) by treatment of the cells with an inhibitor of glycosphingolipid synthase or alpha-galactosidase A led to decreased expression of adhesion molecules. Plasma from Fabry patients significantly increased ROS generation in endothelial cells when compared with plasma from non-Fabry controls. This effect was not influenced by reduction of intracellular Gb(3). This study provided direct evidence that excess intracellular Gb(3) induces oxidative stress and up-regulates the expression of cellular adhesion molecules in vascular endothelial cells. In addition, other factors in patient's plasma may also contribute to oxidative stress in Fabry vascular endothelial cells.
