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Decreased Nitric Oxide Bioavailability in a Mouse Model of Fabry Disease

Division of Nephrology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan

Correspondence: Dr. James A. Shayman, Nephrology Division, Department of Internal Medicine, University of Michigan, Box 5676, Room 1560 MSRB II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5676. Phone: 734-763-0992; Fax: 734-763-0982; E-mail: jshayman{at}umich.edu

Received for publication November 19, 2008. Accepted for publication May 15, 2009.

Fabry disease is a lysosomal storage disorder that results in an accumulation of globotriaosylceramide in vascular tissue secondary to a deficiency in -galactosidase A. The glycolipid-associated vasculopathy results in strokes and cardiac disease, but the basis for these complications is poorly understood. Recent studies in the -galactosidase A–knockout mouse suggested that a decrease in nitric oxide (NO) bioavailability may play a role in the abnormal thrombosis, atherogenesis, and vasorelaxation that are characteristic of these mice. To understand better the association between impaired NO bioavailability and glycolipid accumulation, we studied -galactosidase A–knockout mice or primary cultures of their aortic endothelial cells. Treatment of knockout mice with a potent inhibitor of glucosylceramide synthase reversed accumulation of globotriaosylceramide but failed to normalize the defect in vasorelaxation. Basal and insulin-stimulated endothelial NO synthase (eNOS) activities in endothelial cells derived from knockout mice were lower than those observed from wild-type mice; normalization of glycolipid only partially reversed this reduction in eNOS activity. The loss of eNOS activity associated with a decrease in high molecular weight caveolin oligomers in endothelial cells and isolated caveolae, suggesting a role for glycolipids in caveolin assembly. Finally, concentrations of ortho-tyrosine and nitrotyrosine in knockout endothelial cells were markedly elevated compared with wild-type endothelial cells. These findings are consistent with a loss of NO bioavailability, associated with eNOS uncoupling, in the -galactosidase A–knockout mouse.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673