Artikel
Angiotensin II type I receptor (AT1R) antibodies induce structural changes of the glycocalyx of human umbilical vein endothelial cells
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Autoren
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Maj Jäpel
- Department of Rheumatology and Clinical Immunology, Universal Medical Center Schleswig-Holstein, Lübeck Campus, Lübeck
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Alexander Hackel
- Department of Rheumatology and Clinical Immunology, Universal Medical Center Schleswig-Holstein, Lübeck Campus, Lübeck
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Benedikt Fels
- Institute of Physiology, University of Lübeck, Lübeck; DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck
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Hanna Graßhoff
- Department of Rheumatology and Clinical Immunology, Universal Medical Center Schleswig-Holstein, Lübeck Campus, Lübeck
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Tanja Lange
- Department of Rheumatology and Clinical Immunology, Universal Medical Center Schleswig-Holstein, Lübeck Campus, Lübeck
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Kristina Kusche-Vihrog
- Institute of Physiology, University of Lübeck, Lübeck; DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck
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Harald Heidecke
- CellTrend GmbH, Luckenwald
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Antje Müller
- Department of Rheumatology and Clinical Immunology, Universal Medical Center Schleswig-Holstein, Lübeck Campus, Lübeck
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Reza Akbarzadeh
- Department of Rheumatology and Clinical Immunology, Universal Medical Center Schleswig-Holstein, Lübeck Campus, Lübeck
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Gabriela Riemekasten
- Department of Rheumatology and Clinical Immunology, Universal Medical Center Schleswig-Holstein, Lübeck Campus, Lübeck
| Veröffentlicht: | 30. August 2023 |
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Gliederung
Text
Introduction: It has been demonstrated that immunization with membrane-embedded Angiotensin II type 1 receptor (AT1R) induces lung inflammation and AT1R antibodies in vivo [1]. Another study showed that IgG isolated from patients with systemic sclerosis containing AT1R antibodies induces activation of human microvascular endothelial cells in vitro [2]. Thus, we hypothesize that antibodies directed against the angiotensin II type 1 director receptor contribute to endothelial dysfunction. A proper endothelial function can be correlated with mechanical properties of the top surface layer (endothelial glycocalyx).
Methods: Human umbilical vein endothelial cells (HUVEC) were isolated from the umbilical cord, cultured on coverslip, and used at passage 2. A monoclonal AT1R antibody (AT1R mAb) and the corresponding isotype control were applied at different concentrations (10, 50, 100 and 200 mg/mL) for 24 hours. To examine the nanomechanical properties (height, stiffness) of the endothelial glycocalyx (eGC) atomic force microscopy (AFM) was used.
Results: Following the in vitro treatment of HUVEC with the AT1R mAb, the height of the eGC decreased by approx. 29% using 10 µg/mL (p<0.0001) and by approx. 15% (p>0.05) using 50 µg/mL. After the treatment with 100 µg/mL and 200 µg/mL the eGC height decreased by approx. 49% (p<0.0001) and approx. 36% (p<0.001), respectively. Accordingly, the stiffness of the eGC increased by approx. 70% (p<0.0001) using 10 µg/mL and approx. 12% (p>0.05) using 50 µg/mL. When applying 100 µg/mL and 200 µg/mL the stiffness increased by approx. 75% (p<0.0001) and approx. 45% (p<0.001), respectively.
Conclusion: Both, decreased height and increased stiffness indicate a dysfunction of the HUVEC glycocalyx which could be mediated by AT1R antibody found in the circulation of patients and healthy individuals. Ongoing experiments using AT1R antagonist and IgG derived from SSc patients will aid to find out if other GPCR antibodies might contribute to structural changes of the eGC.
References
- 1.
- Yue X, Yin J, Wang X, Heidecke H, Hackel AM, Dong X, Kasper B, Wen L, Zhang L, Schulze-Forster K, Junker J, Grasshoff H, Müller A, Wallukat G, Schimke I, Zeiner J, Deckstein LM, Mertens N, Kerstein-Staehle A, Hundt JE, Kostenis E, Yu X, Riemekasten G, Petersen F. Induced antibodies directed to the angiotensin receptor type 1 provoke skin and lung inflammation, dermal fibrosis and act species overarching. Ann Rheum Dis. 2022 May 20;81(9):1281–9. DOI: 10.1136/annrheumdis-2021-222088
- 2.
- Kill A, Tabeling C, Undeutsch R, Kühl AA, Günther J, Radic M, Becker MO, Heidecke H, Worm M, Witzenrath M, Burmester GR, Dragun D, Riemekasten G. Autoantibodies to angiotensin and endothelin receptors in systemic sclerosis induce cellular and systemic events associated with disease pathogenesis. Arthritis Res Ther. 2014 Jan 28;16(1):R29. DOI: 10.1186/ar4457
