背景:动脉粥样硬化(AS)是最常见的心血管疾病,负担非常高。高脂饮食(HFD)是一种流行的饮食行为,而低剂量辐射(LDR)是一种环境物理因素。有证据表明HFD可能会加剧动脉粥样硬化的发作。尚不完全清楚HFD和LDR的联合作用是否对动脉粥样硬化的发展具有潜力。
方法:在本研究中,ApoE-/-小鼠作为动脉粥样硬化模型动物,研究HFD和LDR的联合作用(10×0.01Gy,或20×0.01Gy)对血管病变。多普勒超声成像,H&E染色,油红O染色,西方印迹,和免疫组织化学(IHC)用于评估前动脉粥样硬化作用。LC-MS用于检测非靶向脂质组学。
结果:在累积剂量为0.2Gy的低剂量辐射的长期暴露显著增加了ApoE-/-小鼠的血管僵硬和主动脉损伤的发生。观察到HFD和LDR在动脉粥样硬化发展中的协同作用,这可能与脂质代谢的生态失调和炎症信号系统的刺激有关。此外,LDR而非HFD可以通过增加胞质线粒体DNA的产量以及cGAS蛋白的表达来激活cGAS-STING信号传导。cGAS-STING信号的激活引发IFN-α/-β的释放,它在动脉粥样硬化斑块的形成中起着炎症放大器的作用。
结论:当前的研究为LDR导致动脉粥样硬化发展的风险和机制提供了新的见解,LDR和HFD的联合作用与cGAS-STING信号通路有关。
BACKGROUND: Atherosclerosis (AS) is the most prevalent cardiovascular disease, with an exceptionally high burden. High-fat diet (HFD) is a popular diet behavior, whereas low-dose radiation (LDR) is an environmental physical factor. There is evidence to suggest that an HFD may exacerbate the onset of atherosclerosis. Whether the combination effect of HFD and LDR would have potential on atherosclerosis development remains incompletely unclear.
METHODS: In this study, ApoE-/- mice were used as atherosclerosis model animals to investigate the combination effects of HFD and LDR (10 × 0.01Gy, or 20 × 0.01Gy) on vascular lesions. Doppler ultrasound imaging, H&E staining, oil red O staining, western blotting, and immunohistochemistry (IHC) were used to assess the pro-atherosclerotic effects. LC-MS was used to detect the non-targeted lipidomic.
RESULTS: Long-term exposure of low-dose radiation at an accumulated dose of 0.2Gy significantly increased the occurrence of vascular stiffness and the aortic lesion in ApoE-/- mice. The synergistic effect of HFD and LDR was observed in the development of atherosclerosis, which might be linked to both the dysbiosis of lipid metabolism and the stimulation of the inflammatory signaling system. Moreover, LDR but not HFD can activate the cGAS-STING signaling through increasing the yield of cytosolic mitochondrial DNAs as well as the expression of cGAS protein. The activation of cGAS-STING signal triggers the release of IFN-α/-β, which functions as an inflammatory amplifier in the formation of atherosclerotic plaque.
CONCLUSIONS: The current study offers fresh insights into the risks and mechanism that underlie the development of atherosclerosis by LDR, and there is a combination effect of LDR and HFD with the involvement of cGAS-STING signal pathway.