LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis
| Autor: | Kroone, C., Vos, M., Rademakers, T., Kuijpers, M., Hoogenboezem, M., Buul, J. van, Heemskerk, J.W.M., Ruf, W., Vlieg, A.V., Versteeg, H.H., Goumans, M.J., Vries, C.J.M. de, Kurakula, K., INVENT Consortium |
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| Přispěvatelé: | RS: Carim - B03 Cell biochemistry of thrombosis and haemostasis, Biochemie, MUMC+: HVC Pieken Trombose (9), Medical Biochemistry, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Gastroenterology Endocrinology Metabolism, Landsteiner Laboratory, ACS - Heart failure & arrhythmias, Physiology, ACS - Pulmonary hypertension & thrombosis |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
SMOOTH-MUSCLE-CELLS
LIM-Homeodomain Proteins Muscle Proteins COAGULATION Thromboplastin FACTOR EXPRESSION ACTIVATION 03 medical and health sciences Tissue factor Mice 0302 clinical medicine PROCOAGULANT ACTIVITY Medicine Animals Humans Thrombus Venous Thrombosis Gene knockdown Hemostasis business.industry INDUCTION THROMBOMODULIN Genetic Variation Hematology Articles medicine.disease Thrombosis ENDOTHELIAL-CELLS FHL2 RECEPTORS Venous thrombosis Coagulation MONOCYTES Cancer research Signal transduction business 030215 immunology Transcription Factors |
| Zdroj: | Haematologica-the Hematology Journal, 105(6), 1677-1685. Ferrata Storti Foundation Haematologica Haematologica, 105(6), 1677-1685. Ferrata Storti Foundation INVENT Consortium 2020, ' LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis ', Haematologica, vol. 105, no. 6, pp. 1677-1685 . https://doi.org/10.3324/haematol.2018.203026 Haematologica, 105(6), 1677-1685. FERRATA STORTI FOUNDATION |
| ISSN: | 0390-6078 |
| DOI: | 10.3324/haematol.2018.203026 |
| Popis: | 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 in vascular endothelial and smooth muscle cells. Here, we sought to identify factors that modulate tissue factor gene expression and activity in these vascular cells. The LIM-only protein FHL2 is a scaffolding protein modulating signal transduction pathways with crucial functions in endothelial and smooth muscle cells. However, the role of FHL2 in tissue factor regulation and thrombosis remains unexplored. Using a murine venous thrombosis model in mesenteric vessels, we demonstrated that FHL2 deficiency results in exacerbated thrombus formation. Gain and loss of function experiments revealed that FHL2 represses tissue factor expression in endothelial and smooth muscle cells through inhibition of the transcription factors NFκB and AP-1. Furthermore, we observed that FHL2 interacts with the cytoplasmic tail of tissue factor. In line with our in vivo observations, FHL2 decreases tissue factor activity in endothelial and smooth muscle cells whereas FHL2 knockdown or deficiency results in enhanced tissue factor activity. Finally, FHL2 single nucleotide polymorphism (SNP) rs4851770 was associated with venous thrombosis risk 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 tissue factor-mediated coagulation and identify FHL2 as a novel gene associated with venous thrombosis in man. |
| Databáze: | OpenAIRE |
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