Silencing of the von Willebrand factor gene in proatherothrombotic transgenic mice.

BACKGROUND

Elevated von Willebrand factor (VWF) levels correlate with higher risk of atherosclerosis-related arterial thrombosis (atherothrombosis). Silencing the gene via small-interfering RNAs (siRNAs) could mitigate this risk. Previous studies successfully delivered siRNA to the endothelium of healthy, wild-type (WT) mice using lipid nanoparticles (LNPs).

OBJECTIVES

This study aimed to investigate whether the LNP-siRNA strategy could achieve endothelium-specific -silencing under diseased conditions of prolonged hypercholesterolemia and atherothrombosis-prone vasculature.

METHODS

Female transgenic mice expressing a variant of human (ie, ) and human cholesteryl ester transfer protein (), fed a cholesterol-enriched diet for 18 weeks, received an intravenous injection of LNP-encapsulated siRNA targeting (si) or scrambled control siRNA at 1.5 mg siRNA/kg. For comparison, the same LNP-siRNAs were administered to young, chow-fed WT mice. Plasma VWF and mRNA levels were measured 96 hours after injection, with immunofluorescence analysis of lungs and heart aortic root to assess VWF protein expression.

RESULTS

mice exhibited elevated plasma VWF levels compared with WT mice, alongside hypercholesterolemia and aortic atherosclerosis. si administration led to over 85% reduction in plasma VWF in both strains, with a strong reduction in lung mRNA and VWF protein in the pulmonary endothelium. Similarly, si treatment resulted in the virtual absence of VWF protein in the endothelial lining of the aortic root of both nondiseased (WT mice) and atherosclerotic ( mice) vessel walls.

CONCLUSION

The LNP-siRNA targeting strongly reduced plasma and endothelial VWF in mice with hypercholesterolemia and advanced atherosclerosis, indicating feasibility to target endothelial VWF under proatherothrombotic conditions.