Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-Cho, Tokushima 770-8503, Japan.
Department of Cardio-Diabetes Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-Cho, Tokushima 770-8503, Japan.
Eur Heart J. 2021 Nov 7;42(42):4336-4348. doi: 10.1093/eurheartj/ehab249.
Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis.
Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP.
Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.
与生活方式相关的疾病会促进动脉粥样硬化，这是一种慢性炎症性疾病；然而，其分子机制在很大程度上尚不清楚。在营养过剩的情况下，内源性 DNA 片段会通过 DNA 传感器的识别引发无菌性炎症。在这里，我们研究了干扰素基因刺激物（STING），一种细胞质 DNA 传感器，在动脉粥样硬化形成中的作用。
载脂蛋白 E 缺陷（Apoe-/-）小鼠喂食西方饮食（WTD），一种高胆固醇血症小鼠模型，与野生型（WT）小鼠相比，其主动脉中的巨噬细胞中 STING 表达和 DNA 损伤标志物（如 γH2AX、p53 和单链 DNA（ssDNA）积累）更高。Apoe-/-小鼠主动脉中的 STING 激动剂 cGAMP 水平较高。与对照相比，Apoe-/- 小鼠中 Sting 的基因缺失减少了主动脉弓中的动脉粥样硬化病变、斑块中的脂质和巨噬细胞积累以及主动脉中的炎症分子表达。使用特异性抑制剂 C-176 抑制 STING 可改善 Apoe-/- 小鼠的动脉粥样硬化形成。相比之下，Apoe-/- 小鼠中骨髓特异性 STING 表达刺激了动脉粥样硬化形成。STING 的表达或缺失不影响代谢参数和血压。体外研究表明，cGAMP 或线粒体 DNA 激活 STING 可加速小鼠和人巨噬细胞中炎症分子的表达（例如 TNF-α 或 IFN-β）。核因子-κB 和 TANK 结合激酶 1 的激活参与了 STING 相关的血管炎症和巨噬细胞激活。此外，人颈动脉粥样硬化病变中表达 STING 和 cGAMP。
干扰素基因刺激物刺激巨噬细胞的促炎激活，导致动脉粥样硬化的发展。干扰素基因刺激物信号通路可能成为动脉粥样硬化的潜在治疗靶点。
