Severe endothelial dysfunction in the aorta of a mouse model of Fabry disease; partial prevention by N‐butyldeoxynojirimycin treatment
- 25 December 2006
- journal article
- Published by Wiley in Journal of Inherited Metabolic Disease
- Vol. 30 (1) , 79-87
- https://doi.org/10.1007/s10545-006-0473-y
Abstract
Summary: Objective: Fabry disease results from α‐gala‐ ctosidase A deficiency and is characterized by the lysosomal accumulation of globotriaosylceramide. Globotriaosylceramide storage predominantly affects endothelial cells, altering vascular wall morphology and vasomotor function. Our objective was to investigate aortic globotriaosylceramide levels, morphology and function in a mouse model of Fabry disease, and the effect of substrate reduction therapy, using the glycosphingolipid biosynthesis inhibitor N‐butyldeoxynojirimycin. Methods and results: Mice used were C57BL/6J and α‐galactosidase A knockout (Fabry). We show progressive accumulation of aortic globotriaosylceramide throughout the lifespan of untreated Fabry mice (55‐fold elevation at 2 months increasing to 187‐fold by 19 months), localized to endothelial and vascular smooth‐muscle cells; there was no effect on vascular wall morphology in young Fabry mice. In old mice, storage resulted in intimal thickening. Endothelial function declined with age in Fabry mouse aorta. Aortae from N‐butyldeoxynojirimycin‐treated Fabry mice at 19 months of age had reduced endothelial globotriaosylceramide storage, fewer morphological abnormalities and less severe vasomotor dysfunction compared with untreated littermates. Conclusion: We provide evidence of a novel vascular phenotype in the Fabry mouse that has relevance to vascular disease in Fabry patients. N‐Butyldeoxynojirimycin treatment partially prevented the phenotype in the Fabry mouse by reducing endothelial globotriaosylceramide storage.Keywords
This publication has 39 references indexed in Scilit:
- Enzyme Replacement for Lysosomal DiseasesAnnual Review of Medicine, 2006
- α-Galactosidase A Deficiency Accelerates Atherosclerosis in Mice With Apolipoprotein E DeficiencyCirculation, 2005
- Mechanisms of Increased Vascular Superoxide Production in Human Diabetes MellitusCirculation, 2002
- Non-invasive evaluation of arterial involvement in patients affected with Fabry diseaseJournal of Medical Genetics, 2001
- Fabry Disease (α-Galactosidase A Deficiency)Published by Elsevier ,2001
- Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivationJournal of Clinical Investigation, 2000
- Tetrahydrobiopterin restores endothelial function in hypercholesterolemia.Journal of Clinical Investigation, 1997
- Cerebrovascular complications of Fabry's diseaseAnnals of Neurology, 1996
- Amelioration by L-Arginine of a Dysfunctional Arginine/Nitric Oxide Pathway in Diabetic EndotheliumJournal of Cardiovascular Pharmacology, 1995