Low-dose radiation promotes high-fat diet-induced atherosclerosis by activating cGAS signal pathway

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. Conclusion: 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.