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LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis
Bleeding disorders and thrombotic complications are major causes of morbidity and mortality with many cases being unexplained. Thrombus formation involves aberrant expression and activation of tissue factor (TF) in vascular endothelial and smooth muscle cells. Here, we sought to identify factors tha...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ferrata Storti Foundation
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271603/ https://www.ncbi.nlm.nih.gov/pubmed/31467128 http://dx.doi.org/10.3324/haematol.2018.203026 |
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author | Kroone, Chantal Vos, Mariska Rademakers, Timo Kuijpers, Marijke Hoogenboezem, Mark van Buul, Jaap Heemskerk, Johan W.M. Ruf, Wolfram van Hylckama Vlieg, Astrid Versteeg, Henri H. Goumans, Marie-José de Vries, Carlie J.M. Kurakula, Kondababu |
author_facet | Kroone, Chantal Vos, Mariska Rademakers, Timo Kuijpers, Marijke Hoogenboezem, Mark van Buul, Jaap Heemskerk, Johan W.M. Ruf, Wolfram van Hylckama Vlieg, Astrid Versteeg, Henri H. Goumans, Marie-José de Vries, Carlie J.M. Kurakula, Kondababu |
author_sort | Kroone, Chantal |
collection | PubMed |
description | Bleeding disorders and thrombotic complications are major causes of morbidity and mortality with many cases being unexplained. Thrombus formation involves aberrant expression and activation of tissue factor (TF) in vascular endothelial and smooth muscle cells. Here, we sought to identify factors that modulate TF gene expression and activity in these vascular cells. The LIM-only protein FHL2 is a scaffolding protein that modulates signal transduction pathways with crucial functions in endothelial and smooth muscle cells. However, the role of FHL2 in TF regulation and thrombosis remains unexplored. Using a murine model of venous thrombosis in mesenteric vessels, we demonstrated that FHL2 deficiency results in exacerbated thrombus formation. Gain- and loss-of-function experiments revealed that FHL2 represses TF expression in endothelial and smooth muscle cells through inhibition of the transcription factors nuclear factor κB and activating protein-1. Furthermore, we observed that FHL2 interacts with the cytoplasmic tail of TF. In line with our in vivo observations, FHL2 decreases TF activity in endothelial and smooth muscle cells whereas FHL2 knockdown or deficiency results in enhanced TF activity. Finally, the FHL2 single nucleotide polymorphism rs4851770 was associated with the risk of venous thrombosis in a large population of venous thrombosis cases and control subjects from 12 studies (INVENT consortium). Altogether, our results highlight functional involvement of FHL2 in TF-mediated coagulation and identify FHL2 as a novel gene associated with venous thrombosis in humans. |
format | Online Article Text |
id | pubmed-7271603 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Ferrata Storti Foundation |
record_format | MEDLINE/PubMed |
spelling | pubmed-72716032020-06-12 LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis Kroone, Chantal Vos, Mariska Rademakers, Timo Kuijpers, Marijke Hoogenboezem, Mark van Buul, Jaap Heemskerk, Johan W.M. Ruf, Wolfram van Hylckama Vlieg, Astrid Versteeg, Henri H. Goumans, Marie-José de Vries, Carlie J.M. Kurakula, Kondababu Haematologica Articles Bleeding disorders and thrombotic complications are major causes of morbidity and mortality with many cases being unexplained. Thrombus formation involves aberrant expression and activation of tissue factor (TF) in vascular endothelial and smooth muscle cells. Here, we sought to identify factors that modulate TF gene expression and activity in these vascular cells. The LIM-only protein FHL2 is a scaffolding protein that modulates signal transduction pathways with crucial functions in endothelial and smooth muscle cells. However, the role of FHL2 in TF regulation and thrombosis remains unexplored. Using a murine model of venous thrombosis in mesenteric vessels, we demonstrated that FHL2 deficiency results in exacerbated thrombus formation. Gain- and loss-of-function experiments revealed that FHL2 represses TF expression in endothelial and smooth muscle cells through inhibition of the transcription factors nuclear factor κB and activating protein-1. Furthermore, we observed that FHL2 interacts with the cytoplasmic tail of TF. In line with our in vivo observations, FHL2 decreases TF activity in endothelial and smooth muscle cells whereas FHL2 knockdown or deficiency results in enhanced TF activity. Finally, the FHL2 single nucleotide polymorphism rs4851770 was associated with the risk of venous thrombosis in a large population of venous thrombosis cases and control subjects from 12 studies (INVENT consortium). Altogether, our results highlight functional involvement of FHL2 in TF-mediated coagulation and identify FHL2 as a novel gene associated with venous thrombosis in humans. Ferrata Storti Foundation 2020-06 /pmc/articles/PMC7271603/ /pubmed/31467128 http://dx.doi.org/10.3324/haematol.2018.203026 Text en Copyright© 2020 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher. |
spellingShingle | Articles Kroone, Chantal Vos, Mariska Rademakers, Timo Kuijpers, Marijke Hoogenboezem, Mark van Buul, Jaap Heemskerk, Johan W.M. Ruf, Wolfram van Hylckama Vlieg, Astrid Versteeg, Henri H. Goumans, Marie-José de Vries, Carlie J.M. Kurakula, Kondababu LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis |
title | LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis |
title_full | LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis |
title_fullStr | LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis |
title_full_unstemmed | LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis |
title_short | LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis |
title_sort | lim-only protein fhl2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and fhl2 genetic variation associates with human venous thrombosis |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271603/ https://www.ncbi.nlm.nih.gov/pubmed/31467128 http://dx.doi.org/10.3324/haematol.2018.203026 |
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