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01-01-2013 | Original Contribution

Pathologic endothelial response and impaired function of circulating angiogenic cells in patients with Fabry disease

Authors: Johan M. Lorenzen, Bernd Dietrich, Jan Fiedler, Virginija Jazbutyte, Felix Fleissner, Nicola Karpinski, Frank Weidemann, Christoph Wanner, Esther Asan, Massimiliano Caprio, Georg Ertl, Johann Bauersachs, Thomas Thum

Published in: Basic Research in Cardiology | Issue 1/2013

Abstract

Fabry disease is an X-chromosomal recessive deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal). This results in an accumulation of globotriaosylceramide (GL-3) in a variety of cells often with subsequent functional impairment. Here, the impact of Fabry disease on the biology of circulating angiogenic cells (CACs) and the endothelial response to transient ischemia was investigated. Untreated patients with Fabry disease (n = 26), patients after initiation of alpha-Gal enzyme replacement therapy (ERT) (n = 16) and healthy controls (n = 26) were investigated. Endothelial function was assessed by the EndoPAT2000 device. CAC numbers were assessed by flow-cytometry, CAC function by a modified Boyden chamber assay. Fabry patients showed a pathologic endothelial response, which normalized after ERT. CACs were increased in number, but functionally impaired. Immunofluorescence and electron microscopy identified an accumulation of GL-3 in Fabry CACs. ERT attenuated CAC dysfunction and improved markers of oxidative stress response in Fabry patients via a reduction in GL-3 accumulation in vitro and in vivo. Silencing of alpha-Gal in healthy CACs impaired their migratory capacity underlining a key role of this enzyme for CAC function. CAC supernatant as well as CACs from Fabry patients impaired angiogenesis and migratory capacity of HUVECs providing a mechanistic link between CAC and endothelial dysfunction. CAC adhesion to TNF-α pre-stimulated HUVECs and tube formation was impaired by alpha-Gal knockdown. Fabry patients show a dysfunction of CAC and a pathologic endothelial response. ERT improves CAC and endothelial function and thus may attenuate development of cardiovascular disease in the long term in this patient population.

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Title: Pathologic endothelial response and impaired function of circulating angiogenic cells in patients with Fabry disease
Authors: Johan M. Lorenzen
Bernd Dietrich
Jan Fiedler
Virginija Jazbutyte
Felix Fleissner
Nicola Karpinski
Frank Weidemann
Christoph Wanner
Esther Asan
Massimiliano Caprio
Georg Ertl
Johann Bauersachs
Thomas Thum
Publication date: 01-01-2013
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 1/2013
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-012-0311-3

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Pathologic endothelial response and impaired function of circulating angiogenic cells in patients with Fabry disease

Abstract

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