Journal article
Cellular fibronectin promotes deep vein thrombosis in diet-induced obese mice
Journal of thrombosis and haemostasis, Vol.19(3), pp.814-821
03/01/2021
DOI: 10.1111/jth.15206
PMCID: PMC8527852
PMID: 33300307
Abstract
Background Overweight and obesity are significant risk factors for deep vein thrombosis (DVT). Cellular fibronectin containing extra domain A (Fn-EDA), an endogenous ligand for toll-like-receptor 4 (TLR4), contributes to thrombo-inflammation. The role of Fn-EDA in the modulation of DVT is not elucidated yet.
Objective To determine whether Fn-EDA promotes DVT in the context of diet-induced obesity.
Methods Wild-type (WT) and Fn-EDA-deficient mice were either fed control or high-fat (HF) diet for 12 weeks. DVT was induced by inferior vena cava (IVC) stenosis and evaluated after 48 hours. Cellular Fn-EDA levels in the plasma of venous thromboembolism (VTE) patients were measured by sandwich ELISA.
Results We found that cellular Fn-EDA levels were significantly elevated in VTE patients' plasma and positively correlated with body mass index. HF diet-fed WT mice exhibited increased DVT susceptibility compared with control diet-fed WT mice. In contrast, HF diet-fed Fn-EDA-deficient mice exhibited significantly reduced thrombus weight and decreased incidence (%) of DVT compared with HF diet-fed WT mice concomitant with reduced neutrophil content and citrullinated histone H3-positive cells (a marker of NETosis) in IVC thrombus. Exogenous cellular Fn-EDA potentiated NETosis in neutrophils stimulated with thrombin-activated platelets via TLR4. Genetic deletion of TLR4 in Fn-EDA(+) mice (constitutively express Fn-EDA in plasma and tissues), but not in Fn-EDA-deficient mice, reduced DVT compared with respective controls.
Conclusion These results demonstrate a previously unknown role of Fn-EDA in the DVT exacerbation, which may be an essential mechanism promoting DVT in the setting of diet-induced obesity.
Details
- Title: Subtitle
- Cellular fibronectin promotes deep vein thrombosis in diet-induced obese mice
- Creators
- Nirav Dhanesha - University of IowaManish Jain - University of IowaPrakash Doddapattar - University of IowaAnetta Undas - Jagiellonian UniversityAnil K. Chauhan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of thrombosis and haemostasis, Vol.19(3), pp.814-821
- DOI
- 10.1111/jth.15206
- PMID
- 33300307
- PMCID
- PMC8527852
- NLM abbreviation
- J Thromb Haemost
- ISSN
- 1538-7933
- eISSN
- 1538-7836
- Publisher
- Wiley
- Number of pages
- 8
- Grant note
- American Society of Hematology 18EIA33900009 / American Heart Association R35HL139926; R01NS109910; U01NS113388 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 03/01/2021
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359956802771
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