Abstract
Fabry disease (FD) is an X-linked multisystemic lysosomal storage disease due to a deficiency of α-galactosidase A (GLA/AGAL). Progressive cellular accumulation of the AGAL substrate globotriaosylceramide (Gb3) leads to endothelial dysfunction. Here, we analyzed endothelial function in vivo and in vitro in an AGAL-deficient genetic background to identify the processes underlying this small vessel disease. Arterial stiffness and endothelial function was prospectively measured in five males carrying GLA variants (control) and 22 FD patients under therapy. AGAL-deficient endothelial cells (EA.hy926) and monocytes (THP1) were used to analyze endothelial glycocalyx structure, function, and underlying inflammatory signals. Glycocalyx thickness and small vessel function improved significantly over time (p<0.05) in patients treated with enzyme replacement therapy (ERT, n=16) and chaperones (n=6). AGAL-deficient endothelial cells showed reduced glycocalyx and increased monocyte adhesion (p<0.05). In addition, increased expression of angiopoietin-2, heparanase and NF-κB was detected (all p<0.05). Incubation of wild-type endothelial cells with pathological globotriaosylsphingosine concentrations resulted in comparable findings. Treatment of AGAL-deficient cells with recombinant AGAL (p<0.01), heparin (p<0.01), anti-inflammatory (p<0.001) and antioxidant drugs (p<0.05), and a specific inhibitor (razuprotafib) of angiopoietin-1 receptor (Tie2) (p<0.05) improved glycocalyx structure and endothelial function in vitro. We conclude that chronic inflammation, including the release of heparanases, appears to be responsible for the degradation of the endothelial glycocalyx and may explain the endothelial dysfunction in FD. This process is partially reversible by FD-specific and anti-inflammatory treatment, such as targeted protective Tie2 treatment.
Highlights
Fabry disease (FD; Online Mendelian Inheritance in Man [OMIM] no. 301500) is an X-linked inherited disorder caused by a lack of the lysosomal enzyme a-galactosidase A (AGAL; EC 3.2.1.22) activity
Untreated males (n=5) carrying genetic variants of unknown significance (GVUS) within the GLA gene (p.S126G and p.A143T) with enzymatic AGAL activities within the reference range, normal lyso-Gb3 values, lacking FD-typical manifestations and symptoms served as controls
Our main results are as follows: 1) Glycocalyx thickness and red blood cell (RBC) count in small vascular vessels in patients with FD improved after FD-specific treatment with enzyme replacement therapy (ERT) or migalastat in vivo
Summary
Fabry disease (FD; Online Mendelian Inheritance in Man [OMIM] no. 301500) is an X-linked inherited disorder caused by a lack of the lysosomal enzyme a-galactosidase A (AGAL; EC 3.2.1.22) activity. 301500) is an X-linked inherited disorder caused by a lack of the lysosomal enzyme a-galactosidase A (AGAL; EC 3.2.1.22) activity. The enzymatic deficiency leads to a lysosomal accumulation of the AGAL substrate globotriaosylceramide (Gb3) in most cell types of affected patients, including cardiac, renal, neuronal and vascular cells. The progressive accumulation results in a multisystemic disorder with early cerebrovascular events, heart failure, cardiac arrhythmia, and end-stage renal disease with a mean reduction of lifespan by 10 to 15 years [1]. A thicker glycocalyx promotes vasculoprotective functions, whereas a degradation of the endothelial glycocalyx barrier results in an increased permeability for macromolecules and an increased leukocyte and platelet adhesion to the endothelium [12,13,14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
