Abstract
Background: Human coagulation factor (F) XI deficiency, a defect of the contact activation system, protects against venous thrombosis, stroke, and heart attack, whereas FXII, plasma prekallikrein, or kininogen deficiencies are asymptomatic. FXI deficiency, inhibition of FXI production, activated FXI (FXIa) inhibitors, and antibodies to FXI that interfere with FXI/FXII interactions reduce experimental thrombosis and inflammation. FXI inhibitors are antithrombotic in patients, and FXI and FXII deficiencies are atheroprotective in apolipoprotein E–deficient mice. Objectives: Investigate the effects of pharmacological targeting of FXI in experimental models of atherogenesis and established atherosclerosis. Methods and Results: Low-density lipoprotein receptor-knockout (Ldlr−/−) mice were administered high-fat diet (HFD) for 8 weeks; concomitantly, FXI was targeted with anti-FXI antibody (14E11) or FXI antisense oligonucleotide (ASO). 14E11 and FXI-ASO reduced atherosclerotic lesion area in proximal aortas when compared with controls, and 14E11 also reduced aortic sinus lesions. In an established disease model, in which therapy was given after atherosclerosis had developed, Ldlr−/− mice were fed HFD for 8 weeks and then administered 14E11 or FXI-ASO weekly until 16 weeks on HFD. In this established disease model, 14E11 and FXI-ASO reduced atherosclerotic lesion area in proximal aortas, but not in aortic sinus. In cultures of human endothelium, FXIa exposure disrupted VE-Cadherin expression and increased endothelial lipoprotein permeability. Strikingly, we found that 14E11 prevented the disruption of VE-Cadherin expression in aortic sinus lesions observed in the atherogenesis mouse model. Conclusion: Pharmacological targeting of FXI reduced atherogenesis in Ldlr−/− mice. Interference with the contact activation system may safely reduce development or progression of atherosclerosis.
Original language | English (US) |
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Pages (from-to) | 1001-1017 |
Number of pages | 17 |
Journal | Journal of Thrombosis and Haemostasis |
Volume | 19 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2021 |
Keywords
- atherosclerosis
- contact activation
- factor XI
- obesity
- vascular permeability
ASJC Scopus subject areas
- Hematology