Advertisement

Fabry Disease pp 365-377 | Cite as

Experimental Studies in Mice on the Vasculopathy of Fabry Disease

  • James A. ShaymanEmail author
Chapter

Abstract

Understanding the basis for the vasculopathy associated with Fabry disease is an important challenge. The α-galactosidase A (Gla) knockout mouse has provided an important tool for the identification of experimental models that may phenocopy the human disease. Specifically, three in vivo models of vascular disease have been identified in the Gla null mouse. These models include oxidant induced thrombosis, accelerated atherogenesis, and impaired vascular reactivity. Aberrant endothelial cell function underlies the basis for these abnormalities. The characterization of these models has led to the identification of the uncoupling of endothelial nitric oxide synthase within the endothelium with the subsequent generation of reactive oxidant species as a likely mechanism underlying the vasculopathy of Fabry disease. More recent work in the exploration of the nexus between Gla deficiency and vasculopathy has followed from the establishment of an in vitro model of Fabry disease. In this chapter the development and characterization of these models is discussed and a model tying glycosphingolipid accumulation to eNOS uncoupling is proposed.

Keywords

Fabry disease Globotriaosylceramide D-threo-ethylenedioxylphenyl-2-palmitoylamino-3-pyrrolidino-propanol Endothelial  nitric  oxide  synthase  Endothelium 

References

  1. 1.
    Eng CM, Fletcher J, Wilcox WR, Waldek S, Scott CR, Sillence DO, Breunig F, Charrow J, Germain DP, Nicholls K, Banikazemi M (2007) Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 30:184–192PubMedCrossRefGoogle Scholar
  2. 2.
    DeGraba T, Azhar S, Dignat-George F, Brown E, Boutiere B, Altarescu G, McCarron R, Schiffmann R (2000) Profile of endothelial and leukocyte activation in Fabry patients. Ann Neurol 47:229–233PubMedCrossRefGoogle Scholar
  3. 3.
    Moore DF, Scott LT, Gladwin MT, Altarescu G, Kaneski C, Suzuki K, Pease-Fye M, Ferri R, Brady RO, Herscovitch P, Schiffmann R (2001) Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabry disease: reversal by enzyme replacement therapy. Circulation 104:1506–1512PubMedCrossRefGoogle Scholar
  4. 4.
    Moore DF, Herscovitch P, Schiffmann R (2001) Selective arterial distribution of cerebral hyperperfusion in Fabry disease. J Neuroimaging 11:303–307PubMedCrossRefGoogle Scholar
  5. 5.
    Altarescu G, Moore DF, Pursley R, Campia U, Goldstein S, Bryant M, Panza JA, Schiffmann R (2001) Enhanced endothelium-dependent vasodilation in Fabry disease. Stroke 32: 1559–1562PubMedCrossRefGoogle Scholar
  6. 6.
    Elliott PM, Kindler H, Shah JS, Sachdev B, Rimoldi OE, Thaman R, Tome MT, McKenna WJ, Lee P, Camici PG (2006) Coronary microvascular dysfunction in male patients with Anderson-Fabry disease and the effect of treatment with alpha galactosidase A. Heart 92:357–360PubMedCrossRefGoogle Scholar
  7. 7.
    Dimitrow PP, Krzanowski M, Undas A (2005) Reduced coronary flow reserve in Anderson-Fabry disease measured by transthoracic Doppler echocardiography. Cardiovasc Ultrasound 3:11PubMedCrossRefGoogle Scholar
  8. 8.
    Stemper B, Hilz MJ (2003) Postischemic cutaneous hyperperfusion in the presence of forearm hypoperfusion suggests sympathetic vasomotor dysfunction in Fabry disease. J Neurol 250:970–976PubMedCrossRefGoogle Scholar
  9. 9.
    Eitzman DT, Bodary PF, Shen Y, Khairallah CG, Wild SR, Abe A, Shaffer-Hartman J, Shayman JA (2003) Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. J Am Soc Nephrol 14:298–302PubMedCrossRefGoogle Scholar
  10. 10.
    Shen Y, Bodary PF, Vargas FB, Homeister JW, Gordon D, Ostenso KA, Shayman JA, Eitzman DT (2006) Alpha-galactosidase A deficiency leads to increased tissue fibrin deposition and thrombosis in mice homozygous for the factor V Leiden mutation. Stroke 37:1106–1108PubMedCrossRefGoogle Scholar
  11. 11.
    Bodary PF, Shen Y, Vargas FB, Bi X, Ostenso KA, Gu S, Shayman JA, Eitzman DT (2005) Alpha-galactosidase A deficiency accelerates atherosclerosis in mice with apolipoprotein E deficiency. Circulation 111:629–632PubMedCrossRefGoogle Scholar
  12. 12.
    Park JL, Whitesall SE, D’Alecy LG, Shu L, Shayman JA (2008) Vascular dysfunction in the alpha-galactosidase A-knockout mouse is an endothelial cell-, plasma membrane-based defect. Clin Exp Pharmacol Physiol 35:1156–1163PubMedCrossRefGoogle Scholar
  13. 13.
    Shu L, Murphy HS, Cooling L, Shayman JA (2005) An in vitro model of Fabry disease. J Am Soc Nephrol 16:2636–2645PubMedCrossRefGoogle Scholar
  14. 14.
    Shu L, Shayman JA (2007) Caveolin-associated accumulation of globotriaosylceramide in the vascular endothelium of alpha-galactosidase A null mice. J Biol Chem 282:20960–20967PubMedCrossRefGoogle Scholar
  15. 15.
    Lee L, Abe A, Shayman JA (1999) Improved inhibitors of glucosylceramide synthase. J Biol Chem 274:14662–14669PubMedCrossRefGoogle Scholar
  16. 16.
    Abe A, Arend LJ, Lee L, Lingwood C, Brady RO, Shayman JA (2000) Glycosphingolipid depletion in fabry disease lymphoblasts with potent inhibitors of glucosylceramide synthase. Kidney Int 57:446–454PubMedCrossRefGoogle Scholar
  17. 17.
    Abe A, Gregory S, Lee L, Killen PD, Brady RO, Kulkarni A, Shayman JA (2000) Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation. J Clin Invest 105:1563–1571PubMedCrossRefGoogle Scholar
  18. 18.
    Shu L, Park JL, Byun J, Pennathur S, Kollmeyer J, Shayman JA (2009) Decreased nitric oxide bioavailability in a mouse model of Fabry disease. J Am Soc Nephrol 20(9):1975–1985PubMedCrossRefGoogle Scholar
  19. 19.
    Parton RG, Hanzal-Bayer M, Hancock JF (2006) Biogenesis of caveolae: a structural model for caveolin-induced domain formation. J Cell Sci 119:787–796PubMedCrossRefGoogle Scholar
  20. 20.
    Tagawa A, Mezzacasa A, Hayer A, Longatti A, Pelkmans L, Helenius A (2005) Assembly and trafficking of caveolar domains in the cell: caveolae as stable, cargo-triggered, vesicular transporters. J Cell Biol 170:769–779PubMedCrossRefGoogle Scholar
  21. 21.
    Monier S, Dietzen DJ, Hastings WR, Lublin DM, Kurzchalia TV (1996) Oligomerization of VIP21-caveolin in vitro is stabilized by long chain fatty acylation or cholesterol. FEBS Lett 388:143–149PubMedCrossRefGoogle Scholar
  22. 22.
    Pol A, Martin S, Fernandez MA, Ingelmo-Torres M, Ferguson C, Enrich C, Parton RG (2005) Cholesterol and fatty acids regulate dynamic caveolin trafficking through the Golgi complex and between the cell surface and lipid bodies. Mol Biol Cell 16:2091–2105PubMedCrossRefGoogle Scholar
  23. 23.
    Liu J, Garcia-Cardena G, Sessa WC (1996) Palmitoylation of endothelial nitric oxide synthase is necessary for optimal stimulated release of nitric oxide: implications for caveolae localization. Biochemistry 35:13277–13281PubMedCrossRefGoogle Scholar
  24. 24.
    Robinson LJ, Michel T (1995) Mutagenesis of palmitoylation sites in endothelial nitric oxide synthase identifies a novel motif for dual acylation and subcellular targeting. Proc Natl Acad Sci USA 92:11776–11780PubMedCrossRefGoogle Scholar
  25. 25.
    Shaul PW (2002) Regulation of endothelial nitric oxide synthase: location, location, location. Annu Rev Physiol 64:749–774PubMedCrossRefGoogle Scholar

Copyright information

© Springer Netherlands 2010

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of MichiganAnn ArborUSA

Personalised recommendations