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α-galactosidase A deficiency promotes von Willebrand factor secretion in models of Fabry disease.
Kang, Justin J; Kaissarian, Nayiri M; Desch, Karl C; Kelly, Robert J; Shu, Liming; Bodary, Peter F; Shayman, James A.
Afiliación
  • Kang JJ; School of Kinesiology, University of Michigan, Ann Arbor, Michigan, USA.
  • Kaissarian NM; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.
  • Desch KC; Department of Pediatrics and Communicable Disease, University of Michigan, Ann Arbor, Michigan, USA.
  • Kelly RJ; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.
  • Shu L; Division of Nephrology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
  • Bodary PF; School of Kinesiology, University of Michigan, Ann Arbor, Michigan, USA.
  • Shayman JA; Division of Nephrology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA. Electronic address: jshayman@umich.edu.
Kidney Int ; 95(1): 149-159, 2019 01.
Article en En | MEDLINE | ID: mdl-30470436
Fabry disease results from loss of activity of the lysosomal enzyme α-galactosidase A (GLA), leading to the accumulation of globoseries glycosphingolipids in vascular endothelial cells. Thrombosis and stroke are life-threatening complications of Fabry disease; however, the mechanism of the vasculopathy remains unclear. We explored the relationship between GLA deficiency and endothelial cell von Willebrand factor (VWF) secretion in in vivo and in vitro models of Fabry disease. Plasma VWF was significantly higher at two months and increased with age in Gla-null compared to wild-type mice. Disruption of GLA in a human endothelial cell line by siRNA and CRISPR/Cas9 resulted in a 3-fold and 5-fold increase in VWF secretion, respectively. The increase in VWF levels was associated with decreased endothelial nitric oxide synthase (eNOS) activity in both in vitro models. Pharmacological approaches that increase nitric oxide bioavailability or decrease reactive oxygen species completely normalized the elevated VWF secretion in GLA deficient cells. In contrast, the abnormality was not readily reversed by recombinant human GLA or by inhibition of glycosphingolipid synthesis with eliglustat. These results suggest that GLA deficiency promotes VWF secretion through eNOS dysregulation, which may contribute to the vasculopathy of Fabry disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de von Willebrand / Enfermedad de Fabry / Alfa-Galactosidasa Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Kidney Int Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de von Willebrand / Enfermedad de Fabry / Alfa-Galactosidasa Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Kidney Int Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos