Endothelial-dependent S-Sulfhydration of tissue factor pathway inhibitor regulates blood coagulation
Tissue factor pathway inhibitor (TFPI) is an important regulator of coagulation and a link between inflammation and thrombosis. Here we investigated whether endothelial cell-driven oxidative post-translational modifications could have an impact on TFPI activity. We focused on S-sulfhydration, which...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723000952 |
| _version_ | 1827950723096117248 |
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| author | Janina Wittig Maria-Kyriaki Drekolia Anastasia Kyselova Fredy Delgado Lagos Magdalena L. Bochenek Jiong Hu Katrin Schäfer Ingrid Fleming Sofia-Iris Bibli |
| author_facet | Janina Wittig Maria-Kyriaki Drekolia Anastasia Kyselova Fredy Delgado Lagos Magdalena L. Bochenek Jiong Hu Katrin Schäfer Ingrid Fleming Sofia-Iris Bibli |
| author_sort | Janina Wittig |
| collection | DOAJ |
| description | Tissue factor pathway inhibitor (TFPI) is an important regulator of coagulation and a link between inflammation and thrombosis. Here we investigated whether endothelial cell-driven oxidative post-translational modifications could have an impact on TFPI activity. We focused on S-sulfhydration, which is a hydrogen sulfide-dependent post-translational modification that, in endothelial cells, is regulated by the enzyme cystathionine γ-lyase (CSE). The study made use of human primary endothelial cells and blood from healthy individuals or subjects with atherosclerosis as well as from mice lacking endothelial CSE. TFPI was S-sulfhydrated in endothelial cells from healthy individuals and mice, while the loss of endothelial CSE expression/activity reduced its modification. Non-S-sulfhydrated TFPI was no longer able to interact with factor Xa, which facilitated the activation of tissue factor. Similarly, non-S-sulfhydratable TFPI mutants bound less protein S, while supplementation with hydrogen sulfide donors, preserved TFPI activity. Phenotypically, loss of TFPI S-sulfhydration increased clot retraction, suggesting that this post-translational modification is a new endothelial cell-dependent mechanism that contributes to the regulation of blood coagulation. |
| first_indexed | 2024-04-09T13:29:56Z |
| format | Article |
| id | doaj.art-c64a64aa8ebc45a1b6f1d0275628ebc7 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-09T13:29:56Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-c64a64aa8ebc45a1b6f1d0275628ebc72023-05-10T04:19:08ZengElsevierRedox Biology2213-23172023-06-0162102694Endothelial-dependent S-Sulfhydration of tissue factor pathway inhibitor regulates blood coagulationJanina Wittig0Maria-Kyriaki Drekolia1Anastasia Kyselova2Fredy Delgado Lagos3Magdalena L. Bochenek4Jiong Hu5Katrin Schäfer6Ingrid Fleming7Sofia-Iris Bibli8Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, GermanyInstitute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, GermanyInstitute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, GermanyInstitute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, GermanyDepartment of Cardiology, Cardiology I, University Medical Center Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany; German Center of Cardiovascular Research (DZHK), Partner Site Rhein-Main, GermanyInstitute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany; Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Cardiology I, University Medical Center Mainz, Germany; German Center of Cardiovascular Research (DZHK), Partner Site Rhein-Main, GermanyInstitute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany; German Center of Cardiovascular Research (DZHK), Partner Site Rhein-Main, GermanyInstitute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany; German Center of Cardiovascular Research (DZHK), Partner Site Rhein-Main, Germany; Corresponding author. Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.Tissue factor pathway inhibitor (TFPI) is an important regulator of coagulation and a link between inflammation and thrombosis. Here we investigated whether endothelial cell-driven oxidative post-translational modifications could have an impact on TFPI activity. We focused on S-sulfhydration, which is a hydrogen sulfide-dependent post-translational modification that, in endothelial cells, is regulated by the enzyme cystathionine γ-lyase (CSE). The study made use of human primary endothelial cells and blood from healthy individuals or subjects with atherosclerosis as well as from mice lacking endothelial CSE. TFPI was S-sulfhydrated in endothelial cells from healthy individuals and mice, while the loss of endothelial CSE expression/activity reduced its modification. Non-S-sulfhydrated TFPI was no longer able to interact with factor Xa, which facilitated the activation of tissue factor. Similarly, non-S-sulfhydratable TFPI mutants bound less protein S, while supplementation with hydrogen sulfide donors, preserved TFPI activity. Phenotypically, loss of TFPI S-sulfhydration increased clot retraction, suggesting that this post-translational modification is a new endothelial cell-dependent mechanism that contributes to the regulation of blood coagulation.http://www.sciencedirect.com/science/article/pii/S2213231723000952TFPIEndothelial CSES-sulfhydrationCoagulation |
| spellingShingle | Janina Wittig Maria-Kyriaki Drekolia Anastasia Kyselova Fredy Delgado Lagos Magdalena L. Bochenek Jiong Hu Katrin Schäfer Ingrid Fleming Sofia-Iris Bibli Endothelial-dependent S-Sulfhydration of tissue factor pathway inhibitor regulates blood coagulation Redox Biology TFPI Endothelial CSE S-sulfhydration Coagulation |
| title | Endothelial-dependent S-Sulfhydration of tissue factor pathway inhibitor regulates blood coagulation |
| title_full | Endothelial-dependent S-Sulfhydration of tissue factor pathway inhibitor regulates blood coagulation |
| title_fullStr | Endothelial-dependent S-Sulfhydration of tissue factor pathway inhibitor regulates blood coagulation |
| title_full_unstemmed | Endothelial-dependent S-Sulfhydration of tissue factor pathway inhibitor regulates blood coagulation |
| title_short | Endothelial-dependent S-Sulfhydration of tissue factor pathway inhibitor regulates blood coagulation |
| title_sort | endothelial dependent s sulfhydration of tissue factor pathway inhibitor regulates blood coagulation |
| topic | TFPI Endothelial CSE S-sulfhydration Coagulation |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723000952 |
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