Journal of lipid and atherosclerosis · 2025
Factor XI Deficiency in apoE/FXI Double-Knockout Mice Decreases Atherosclerosis by Lowering MSR1 mRNA Expression Within the Plaque.
СтатьяНазвание и аннотация: Перевод в очереди
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Shnerb Ganor Reut, Paraboschi Elvezia M, Stefano Duga, Harats Dror, Asselta Rosanna, Schiby Ginette, Leichner Gil S, Anekstein Spigel Mika, Tamarin Ilia, Kandel Kfir Michal, Steinberg David M, Shaish Aviv, Salomon Ophira
Аннотация
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.
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.