Pharmacological targeting of coagulation factor XI mitigates the development of experimental atherosclerosis in low‐density lipoprotein receptor‐deficient mice

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.

Pharmacological Inhibition of Factor XIIa Attenuates Abdominal Aortic Aneurysm, Reduces Atherosclerosis, and Stabilizes Atherosclerotic Plaques

“… 39 Further emphasizing the central role of FXII in mediating atherothrombosis, deficiency of FXII or FXIIa inhibition has been demonstrated to diminish thrombus formation on atherosclerotic plaque material ex vivo. 40 Moreover, a recent study investigating pharmacological inhibition of FXI not only implicated FXI/FXIa in the development of atherosclerosis and thereby indirectly supporting the pathological role of FXIIa within the plaque confines, 41 but also provides further evidence that therapeutic targeting of coagulation factors holds immense potential to impact cardiovascular clinical outcomes.…”

Pharmacological reduction of coagulation factor XI reduces macrophage accumulation and accelerates deep vein thrombosis resolution in a mouse model of venous thrombosis

“…The 5 mg/kg dosage of 14E11 was chosen based on previous work that showed that 14E11 decreased murine FXI levels below the limit of detection. 8 In brief, the dose-finding experiment was performed wherein C57BL/6 mice were injected with a single subcutaneous (SC) dose of 14E11 (5 mg/kg) and APTT was monitored over a period of 10 days. Mice in this study were injected with a single SC dose of 14E11 (5 mg/kg) immediately before inferior vena cava (IVC) constriction surgery.…”

“…7 Previous studies have highlighted the roles of FXI and the contact pathway of coagulation in mediating inflammation in various models of disease. [8][9][10][11] In a mouse model of sepsis, contact pathway inhibition after cecal ligation and perforation was protective and increased survival. 10 Similarly, in a baboon model of Staphylococcus aureus induced sepsis, inhibition of FXI activation by FXIIa attenuated the inflammatory cytokine surge and reduced organ failure and mortality.…”

“…The innate immune system has been shown to play a role in the progression and resolution of thrombi during DVT 7 . Previous studies have highlighted the roles of FXI and the contact pathway of coagulation in mediating inflammation in various models of disease 8–11 . In a mouse model of sepsis, contact pathway inhibition after cecal ligation and perforation was protective and increased survival 10 .…”

The Toll-Like Receptor 2 Ligand Pam2CSK4 Activates Platelet Nuclear Factor-κB and Bruton’s Tyrosine Kinase Signaling to Promote Platelet-Endothelial Cell Interactions

“…To analyze HUVECs permeability to BSA, media containing Evans Blue dye (0.67 mg/ml) and 4% BSA was added to the upper chamber for 30 min at 37°C. Samples from the lower chamber were collected and absorbance at 650 nm was measured using a spectrophotometer (Tecan) as previously described (50).…”