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Severe endothelial dysfunction in the aorta of a mouse model of Fabry disease; partial prevention by N-butyldeoxynojirimycin treatment

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

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.

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Abbreviations

ACh:

acetylcholine

ERT:

enzyme replacement therapy

D-t-EtDO-P4:

D-threo-1-ethylenedioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol

Gb3 :

globotriaosylceramide

GSL:

glycosphingolipid

iNOS:

inducible nitric oxide synthase

NB-DNJ:

N-butyldeoxynojirimycin

NO:

nitric oxide

PE:

phenylephrine

SNP:

sodium nitroprusside

SRT:

substrate reduction therapy

VSM:

vascular smooth muscle

References

  • Abe A, Gregory S, Lee L, et al (2000) Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation. J Clin Invest 105: 1563–1571.

    Article  PubMed  CAS  Google Scholar 

  • Altarescu G, Moore D, Pursley R, et al (2001) Enhanced endothelium-dependent vasodilation in Fabry disease. Stroke 32: 1559–1562.

    PubMed  CAS  Google Scholar 

  • Barngrover D (2002) Fabrazyme—recombinant protein treatment for Fabry's disease. J Biotechnol 95: 280–282.

    PubMed  Google Scholar 

  • Bodary PF, Shen Y, Vargas FB, et al (2005) Alpha-galactosidase A deficiency accelerates atherosclerosis in mice with apolipoprotein E deficiency. Circulation 111: 629–632.

    Article  PubMed  CAS  Google Scholar 

  • Boutouyrie P, Laurent S, Laloux B, et al (2001) Non-invasive evaluation of arterial involvement in patients affected with Fabry disease. J Med Genet 38: 629–631.

    Article  PubMed  CAS  Google Scholar 

  • Brady RO (2006) Enzyme replacement for lysosomal diseases. Annu Rev Med 57: 283–296.

    Article  PubMed  CAS  Google Scholar 

  • Brady RO, Murray G, Moore D, et al (2001) Enzyme replacement therapy in Fabry disease. J Inherit Metab Dis 24: 18–24; discussion 11–12.

    Article  PubMed  CAS  Google Scholar 

  • Chruscinski A, Brede ME, Meinel L, et al (2001) Differential distribution of beta adrenergic receptor subtypes in blood vessels of knockout mice lacking beta 1- or beta 2-adrenergic receptors. Mol Pharmacol 60: 955–962.

    PubMed  CAS  Google Scholar 

  • Cooke J, Andon N, Girerd X, et al (1991) Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation 83: 1057–1062.

    PubMed  CAS  Google Scholar 

  • Cox TM, Lachmann R, Hollak C, et al (2000) Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 355: 1481–1485.

    Article  PubMed  CAS  Google Scholar 

  • DeGraba T, Azhar S, Dignat-George F, et al (2000) Profile of endothelial and leukocyte activation in Fabry patients. Ann Neurol 47: 229–233.

    Article  PubMed  CAS  Google Scholar 

  • Demuth K, Germain DP (2002) Endothelial markers and homocysteine in patients with classic Fabry disease. Acta Paediatr Suppl 91: 57–61.

    Article  PubMed  CAS  Google Scholar 

  • Desnick R, Ioannou Y, Eng C (2001).α-Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 3733–3774.

    Google Scholar 

  • Eitzman DT, Bodary PF, Shen Y, et al (2003) Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. J Am Soc Nephrol 14: 298–302.

    Article  PubMed  CAS  Google Scholar 

  • Garner B, Priestman DA, Stocker R, et al (2002) Increased glycosphingolipid levels in serum and aortae of apolipoprotein E gene knockout mice. J Lipid Res 43: 205–214.

    PubMed  CAS  Google Scholar 

  • Gilligan D, Guetta V, Panza J, et al (1994) Selective loss of microvascular endothelial function in human hypercholesterolemia. Circulation 90: 35–41.

    PubMed  CAS  Google Scholar 

  • Groves P, Kurz S, Just H, et al (1995) Role of endogenous bradykinin in human coronary vasomotor control. Circulation 92: 3424–3430.

    PubMed  CAS  Google Scholar 

  • Guzik TJ, Mussa S, Gastaldi D, et al (2002) Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105: 1656–1662.

    Article  PubMed  CAS  Google Scholar 

  • Itoh Y, Esaki T, Cook M, et al (2001) Local and global cerebral blood flow and glucose utilization in the alpha-galactosidase A knockout mouse model of Fabry disease. J Neurochem 79: 1217–1224.

    Article  PubMed  CAS  Google Scholar 

  • Jeyakumar M, Butters TD, Borja MC, et al (1999) Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin. Proc Natl Acad Sci USA 96: 6388–6393.

    Article  PubMed  CAS  Google Scholar 

  • Mitsias P, Levine S (1996) Cerebrovascular complications of Fabry's disease. Ann Neurol 40: 8–17.

    Article  PubMed  CAS  Google Scholar 

  • Moore D, Scott L, Gladwin M, et al (2001) Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabry disease: reversal by enzyme replacement therapy. Circulation 104: 1506–1512.

    Article  PubMed  CAS  Google Scholar 

  • Moore D, Altarescu G, Pursley R, et al (2002) Arterial wall properties and Womersley flow in Fabry disease. BMC Cardiovasc Disord 2: 1.

    Article  PubMed  Google Scholar 

  • Ohshima T, Murray G, Swaim W, et al (1997) Alpha-galactosidase A deficient mice: a model of Fabry disease. Proc Natl Acad Sci USA 94: 2540–2544.

    Article  PubMed  CAS  Google Scholar 

  • Ohshima T, Schiffmann R, Murray G, et al (1999) Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice. Proc Natl Acad Sci USA 96: 6423–6427.

    Article  PubMed  CAS  Google Scholar 

  • Pieper G, Peltier B (1995) Amelioration by l-arginine of a dysfunctional arginine/nitric oxide pathway in diabetic endothelium. J Cardiovasc Pharmacol 25: 397–403.

    Article  PubMed  CAS  Google Scholar 

  • Pieper G, Siebeneich W, Moore-Hilton G, et al (1997) Reversal by l-arginine of a dysfunctional arginine/nitric oxide pathway in the endothelium of the genetic diabetic BB rat. Diabetologia 40: 910–915.

    Article  PubMed  CAS  Google Scholar 

  • Platt FM, Neises GR, Dwek RA, et al (1994) N-Butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. J Biol Chem 269: 8362–8365.

    PubMed  CAS  Google Scholar 

  • Platt FM, Neises G, Reinkensmeier G, et al (1997a) Prevention of lysosomal storage in Tay–Sachs mice treated with N-butyldeoxynojirimycin. Science 276: 428–431.

    Article  CAS  Google Scholar 

  • Platt FM, Reinkensmeier G, Dwek RA, et al (1997b) Extensive glycosphingolipid depletion in the liver and lymphoid organs of mice treated with N-butyldeoxynojirimycin. J Biol Chem 272: 19365–19372.

    Article  CAS  Google Scholar 

  • Prasad A, Husain S, Schenke W, et al (2000) Contribution of bradykinin receptor dysfunction to abnormal coronary vasomotion in humans. J Am Coll Cardiol 36: 1467–1473.

    Article  PubMed  CAS  Google Scholar 

  • Stroes E, Kastelein J, Cosentino F, et al (1997) Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 99: 41–46.

    Article  PubMed  CAS  Google Scholar 

  • Wing D, Garner B, Hunnam V, et al (2001) High-performance liquid chromatography analysis of ganglioside carbohydrates at the picomole level after ceramide glycanase digestion and fluorescent labeling with 2-aminobenzamide. Anal Biochem 298: 207–217.

    Article  PubMed  CAS  Google Scholar 

  • Wise D, Wallace H, Jellinck E (1962) Angiokeratoma corporis diffusum: a clinical study of eight affected families. Q J Med 31: 177–206.

    PubMed  CAS  Google Scholar 

  • Zervas M, Somers K, Thrall M, et al (2001) Critical role for glycosphingolipids in Niemann–Pick disease type C. Curr Biol 11: 1283–1287.

    Article  PubMed  CAS  Google Scholar 

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Author notes

  1. F. M. Platt

    Present address: Department of Pharmacology, University of Oxford, Oxford, UK

Authors and Affiliations

  1. Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK

    T. Heare, D. A. Priestman, T. D. Butters, R. A. Dwek & F. M. Platt

  2. Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

    N. J. Alp & K. M. Channon

  3. Department of Pharmacology, University of Oxford, Oxford, UK

    D. A. Priestman

  4. Functional Genomics Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA

    A. B. Kulkarni

  5. Blood Diseases Program, National Heart Lung and Blood Institute, Bethesda, Maryland, USA

    P. Qasba

  6. Burdon Sanderson Cardiac Science Centre, University Laboratory of Physiology, University of Oxford, Oxford, UK

    K. Clarke

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  1. T. Heare
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  2. N. J. Alp
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  4. A. B. Kulkarni
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  6. T. D. Butters
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  8. K. Clarke
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  9. K. M. Channon
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  10. F. M. Platt
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Correspondence to F. M. Platt.

Additional information

Communicating editor: Guy Besley

Competing interests: None declared

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Heare, T., Alp, N.J., Priestman, D.A. et al. Severe endothelial dysfunction in the aorta of a mouse model of Fabry disease; partial prevention by N-butyldeoxynojirimycin treatment. J Inherit Metab Dis 30, 79–87 (2007). https://doi.org/10.1007/s10545-006-0473-y

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  • DOI: https://doi.org/10.1007/s10545-006-0473-y

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