| First Author | Shu L | Year | 2009 |
| Journal | J Am Soc Nephrol | Volume | 20 |
| Issue | 9 | Pages | 1975-85 |
| PubMed ID | 19628671 | Mgi Jnum | J:166329 |
| Mgi Id | MGI:4844051 | Doi | 10.1681/ASN.2008111190 |
| Citation | Shu L, et al. (2009) Decreased nitric oxide bioavailability in a mouse model of Fabry disease. J Am Soc Nephrol 20(9):1975-85 |
| abstractText | 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. |
