TY - JOUR
T1 - LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis
AU - INVENT Consortium
AU - Kroone, Chantal
AU - Vos, Mariska
AU - Rademakers, Timo
AU - Kuijpers, Marijke
AU - Hoogenboezem, Mark
AU - Van Buul, Jaap
AU - Heemskerk, Johan W.M.
AU - Ruf, Wolfram
AU - Van Hylckama Vlieg, Astrid
AU - Versteeg, Henri H.
AU - Goumans, Marie José
AU - De Vries, Carlie J.M.
AU - Kurakula, Kondababu
N1 - Funding Information: This work was supported by the research program of the BioMedical Materials Institute, co-funded by the Dutch Ministry of Economic Affairs as a part of Project P1.02 NEXTREAM. This work was also supported by the Rembrandt Institute for Cardiovascular Research (RICS grant 2013), the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation (CVON: 2012-08) and the Dutch Lung Foundation (5.2.17.198JO). Funding Information: This work was supported by the research program of the BioMedical Materials Institute, co-funded by the Dutch Ministry of Economic Affairs as a part of Project P1.02 NEXTREAM. This work was also supported by the Rembrandt Institute for Cardiovascular Research (RICS grant 2013), the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation (CVON: 2012-08) and the Dutch Lung Foundation (5.2.17.198JO).*%blankline%**%blankline%* Publisher Copyright: © 2020 Ferrata Storti Foundation.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085905192&partnerID=8YFLogxK
U2 - https://doi.org/10.3324/haematol.2018.203026
DO - https://doi.org/10.3324/haematol.2018.203026
M3 - Article
C2 - 31467128
SN - 0390-6078
VL - 105
SP - 1677
EP - 1685
JO - Haematologica
JF - Haematologica
IS - 6
ER -