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Abstract
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.

Affiliations

Eunguk Shin 1, Dahye Kim 1, You Yeon Choi 2, HyeSook Youn 3, Ki Moon Seong 2, BuHyun Youn 1 4
1Department of Integrated Biological Science, Pusan National University, Busan, Korea.
2Laboratory of Biological Dosimetry, National Radiation Emergency Medical Center (NREMC), Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, Korea.
3Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Korea.
4Department of Biological Sciences, Pusan National University, Busan, Korea.