Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation
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 v...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:496b45111a274907bee2fcb13ab635262021-12-01T19:38:37ZEndothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation1664-322410.3389/fimmu.2021.789142https://doaj.org/article/496b45111a274907bee2fcb13ab635262021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.789142/fullhttps://doaj.org/toc/1664-3224Fabry 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.Solvey PollmannDavid ScharnetzkiDominique ManikowskiMalte LendersEva BrandFrontiers Media S.A.articleFabry disease (FD)endothelial dysfunctionheparanaseangiopoietin-1-receptorglobotriaosylsphingosine (lyso-Gb3)NF-κBImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Fabry disease (FD) endothelial dysfunction heparanase angiopoietin-1-receptor globotriaosylsphingosine (lyso-Gb3) NF-κB Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
Fabry disease (FD) endothelial dysfunction heparanase angiopoietin-1-receptor globotriaosylsphingosine (lyso-Gb3) NF-κB Immunologic diseases. Allergy RC581-607 Solvey Pollmann David Scharnetzki Dominique Manikowski Malte Lenders Eva Brand Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation |
| description |
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. |
| format |
article |
| author |
Solvey Pollmann David Scharnetzki Dominique Manikowski Malte Lenders Eva Brand |
| author_facet |
Solvey Pollmann David Scharnetzki Dominique Manikowski Malte Lenders Eva Brand |
| author_sort |
Solvey Pollmann |
| title |
Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation |
| title_short |
Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation |
| title_full |
Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation |
| title_fullStr |
Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation |
| title_full_unstemmed |
Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation |
| title_sort |
endothelial dysfunction in fabry disease is related to glycocalyx degradation |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/496b45111a274907bee2fcb13ab63526 |
| work_keys_str_mv |
AT solveypollmann endothelialdysfunctioninfabrydiseaseisrelatedtoglycocalyxdegradation AT davidscharnetzki endothelialdysfunctioninfabrydiseaseisrelatedtoglycocalyxdegradation AT dominiquemanikowski endothelialdysfunctioninfabrydiseaseisrelatedtoglycocalyxdegradation AT maltelenders endothelialdysfunctioninfabrydiseaseisrelatedtoglycocalyxdegradation AT evabrand endothelialdysfunctioninfabrydiseaseisrelatedtoglycocalyxdegradation |
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