Factor XI Deficiency in apoE/FXI Double-Knockout Mice Decreases Atherosclerosis by Lowering MSR1 mRNA Expression Within the Plaque.

Abstract

Objective: Atherosclerosis remains a leading cause of global morbidity and mortality despite cholesterol-lowering drugs and risk factor management. In mice, the absence of coagulation factor XI (FXI) on an apolipoprotein E (apoE)^-/- genetic background has been shown to reduce atherosclerosis. This study examined the molecular pathways through which FXI influences the development of atherosclerosis.

Methods: Laser capture microdissection of plaques from the aortic sinus of apoE/factor XI double knockout (DKO) and apoE knockout (KO) mice was performed at 24 weeks. RNA-seq and the NanoString technique were used to analyze the extracted plaques. Immunohistochemical analysis of the atherosclerotic layers was also conducted.

Results: Among 15,353 expressed genes, 64 showed significant differences between the 2 groups. Gene set enrichment analysis, specifically targeting metabolic pathways, identified upregulation of 8 pathways in atherosclerotic plaques of apoE KO mice; seven of these pathways were classified as related to inflammatory processes. Using an immunological panel containing 547 genes linked to inflammatory and immunological processes, a statistically significant difference was observed in the expression of macrophage scavenger receptor 1 (MSR1) between DKO mice and apoE KO mice (adjusted p-value=0.0015).

Conclusion: Downregulated expression of MSR1 within the atherosclerotic plaques of apoE/FXI DKO mice compared to apoE KO mice was associated with significantly reduced atherosclerosis. Targeting FXI may therefore represent a promising anti-atherogenic therapeutic strategy in addition to its known antithrombotic effects.