LDR-adapted liver-derived cytokines have potential to induce atherosclerosis

Purpose Atherosclerosis is a lipid-driven chronic inflammatory disease that causes cardiovascular diseases (CVD). The association between radiation and atherosclerosis has already been demonstrated; however, the effects of low-dose radiation (LDR) exposure on atherosclerosis have not been reported. Our study aims to propose that LDR may cause atherosclerosis phenotypes by the upregulation of plasminogen activator inhibitor-1 (PAI-1) and downregulation of androgen receptor (AR), which are cytokines secreted from the liver. Methods Low-density lipoprotein (LDL) receptor deficient (Ldlr(-/-)) mice were irradiated at 50 mGy, 100 mGy, and 1000 mGy. LDR irradiated Ldlr(-/-) mice serum was analyzed by cytokine array and proteomics with silver staining. Oil Red O staining and BODIPY staining were performed to determine lipid accumulation in Human umbilical vein endothelial cells (HUVECs). Foam cell formation and monocyte recruitment were assessed through co-culture system with HUVECs and THP-1 cells. Results After irradiation with LDR (100 mGy) the mice showed atherosclerotic phenotypes and through analysis results, we selected regulated cytokines, PAI-1 and AR, and found that these were changed in the liver. LDR-regulated cytokines have the potential to be transported to endothelial cells and induce lipid accumulation, inflammation of monocytes, increased oxidized low-density lipoprotein (oxLDL) and foam cells formation, that were series of phenotypes lead to plaque formation in endothelial cells and induces atherosclerosis. As a further aspect of this study, testosterone undecanoate (TU) was found to pharmacologically inhibit a series of atherosclerotic phenotypes exhibited by LDR. This study suggests a role for PAI-1 and AR in regulating the development of atherosclerosis after LDR exposure. Targeting PAI-1 and AR could serve as an attractive strategy for the management of atherosclerosis following LDR exposure.