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J. Biol. Chem., Vol. 282, Issue 29, 20960-20967, July 20, 2007

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Caveolin-associated Accumulation of Globotriaosylceramide in the Vascular Endothelium of -Galactosidase A Null Mice^*

From the Nephrology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109

Cardiovascular complications, including stroke and myocardial infarction, result in premature mortality in patients with Fabry disease, an X-linked deficiency of -galactosidase A (-Gal A). The enzymatic defect results in the deposition of globotriaosylceramide (Gb3) in the vascular endothelium. To better understand the underlying pathogenesis of Fabry disease, the caveolar lipid content of primary cultured mouse aortic endothelial cells isolated from -Gal A null mice was measured. Lipid mass analysis revealed that the excessive Gb3 in cultured -Gal A-deficient mouse aortic endothelial cells accumulated in endothelial plasma membrane caveolar fractions. The levels of glucosylceramide and lactosylceramide increased in parallel with Gb3 levels in an age-dependent manner, whereas globotetraosylceramide (Gb4) levels reached maximal levels by 6 months of age and then rapidly decreased at older ages. The levels of cholesterol enriched in caveolar membranes declined in parallel with the progressive deposition of Gb3. Depleting Gb3 with recombinant human -Gal A protein or D-threo-ethylenedioxyphenyl-P4, an inhibitor of glucosylceramide synthase, restored cholesterol in cultured -Gal A-deficient mouse aortic endothelial cell caveolae. By contrast, recombinant human -Gal A was less effective in normalizing the cholesterol content. These results demonstrate the caveolar accumulation of glycosphingolipids in an in vitro model of a lysosomal storage disease and raise the possibility that dynamic changes in the composition of plasma membrane lipid microdomains may mediate the endothelial dysfunction seen in Fabry disease.

Received for publication, March 21, 2007 , and in revised form, May 21, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, University of Michigan, Rm. 1560 MSRB II, 1150 West Medical Center Dr., Ann Arbor, MI 48103-0676. Tel.: 734-763-0992; Fax: 734-763-0982; E-mail: jshayman{at}umich.edu.

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