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Haematologica. 2019 Aug 29. pii: haematol.2018.203026. doi: 10.3324/haematol.2018.203026. [Epub ahead of print]

LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and FHL2 genetic variation associates with human venous thrombosis.

Author information

1
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden.
2
Department of Medical Biochemistry, Amsterdam UMC, University of Amsterdam, The Netherlands.
3
Department of Molecular Cell Biology, Sanquin Research, Amsterdam, The Netherlands.
4
Department of Biochemistry, CARIM, Maastricht University, The Netherlands.
5
Dept. of Molecular Cell Biology, Sanquin Research, Amsterdam, The Netherlands.
6
Dept. of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
7
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
8
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
9
Dept. of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands; k.b.kurakula@lumc.nl.

Abstract

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.

KEYWORDS:

Blood Coagulation and Fibrinolysis; Disorders of Coagulation and Fibrinolysis; Vascular Wall Biology and Platelet Adhesion; Venous Thrombosis

PMID:
31467128
DOI:
10.3324/haematol.2018.203026
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