title: Decreased nitric oxide bioavailability in a mouse model of Fabry disease.
abstract: Fabry disease is a lysosomal storage disorder that results in an accumulation of globotriaosylceramide in vascular tissue secondary to a deficiency in alpha-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 alpha-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 alpha-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 alpha-galactosidase A-knockout mouse.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Shu
authors.forename: James L
authors.initials: JL
authors.lastname: Park
authors.forename: Jaeman
authors.initials: J
authors.lastname: Byun
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.forename: Jessica
authors.initials: J
authors.lastname: Kollmeyer
authors.forename: James A
authors.initials: JA
authors.lastname: Shayman
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology*; D000795:Fabry Disease / Q000378:metabolism* / Q000473:pathology*; D005964:Glucosyltransferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D014281:Trihexosylceramides / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology; D000519:alpha-Galactosidase / Q000235:genetics
chemical_list: D051242:Caveolin 1; D014281:Trihexosylceramides; D009569:Nitric Oxide; C018549:globotriaosylceramide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D000519:alpha-Galactosidase; D000109:Acetylcholine