Abstract 11936: Macrophage-Specific DNase II Deficiency Stimulates Atherosclerosis in Apolipoprotein E-deficient Mice

• Published in: Circulation (New York, N.Y.) N.Y.), 2021-11, Vol.144 (Suppl_1), p.A11936-A11936
• Main Authors: Suto, Kumiko, Fukuda, Daiju, Sata, Masataka
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.144.suppl_1.11936

BackgroundAtherosclerosis is a chronic inflammatory disease of the walls of blood vessels. Macrophage activated by endogenous ligands plays an important role in chronic inflammation of blood vessels. Endogenous DNA fragments derived from vascular cells in the presence of various risk factors attract much attention because endogenous DNA fragments, as well as exogenous DNA fragments induce inflammatory responses through the activation of DNA sensor, including Toll-like receptor 9 (TLR9). We hypothesized that DNase II (DN2) in macrophages degradates incorporated DNA fragments, suppressing pro-inflammatory activation of this cell-type and vascular inflammation. Therefore, we investigated the role of DN2 in macrophages in atherogenesis in apolipoprotein e-deficient (ApoE KO). Methods and ResultsMacrophage-specific DN2 deleted ApoE KO mice were generated by cross breeding of DN2-flox mice, LysMCre mice, and ApoE KO mice. Mice obtained by cross breeding of DN2-flox mice and ApoE KO mice were used as the control. All mice were fed a western-type diet from 7 weeks of age and received subcutaneous angiotensin II infusion (1000 ng/kg per minute) from 8 weeks of age for 4 weeks. Macrophage-specific DNase II deletion significantly accelerated atherosclerotic lesion development in the aortic arch in ApoE KO mice (P < 0.05), accompanied with the increase in the expression of MMP-9 and TNF-α (P < 0.05, respectively) in the aorta. DN2-deletion significantly promoted the expression of inflammatory molecules such as MCP-1 (P < 0.01) in macrophages in the response to CpG-ODN 1826, a TLR9 agonist, or mitochondrial DNA. mtDNA promoted IkBα degradation in DN2-deficient macrophages, suggesting that NF-kB signal was related to DNA-induced macrophage activation. ConclusionOur results suggested that macrophage-specific DN2 deletion accelerated pro-inflammatory activation of macrophages in the response to DNA fragments, leading to the development of atherogenesis in ApoE KO mice. DN2 may be a potential therapeutic target for atherosclerosis.