The effect of oxidized low-density lipoprotein (ox-LDL) on radiation-induced endothelial-to-mesenchymal transition

Abstract

Purpose: Radiation-induced cardiovascular disease is a potentially severe side-effect of thoracic radiotherapy treatment. Clinically, this delayed side-effect presents as a form of accelerated atherosclerosis several years after irradiation. As general endothelial dysfunction is known to be an initiating event in radiation-induced vascular damage, we examined the effects of radiation on endothelial cells in radiation-induced atherosclerosis.

Materials and methods: The effects of radiation on human aortic endothelial cells (HAoEC) were assessed by immunoblotting and immunofluorescence assays. Radiation-induced phenotypic changes of endothelial cells (ECs) were examined using atherosclerotic tissues of irradiated apoprotein E null (ApoE^−/−) mice.

Results: Radiation induced the HAoEC to undergo phenotypic conversion to form fibroblast-like cells, called the endothelial-to-mesenchymal transition (EndMT), which leads to the upregulation of mesenchymal cell markers such as alpha-smooth muscle actin (α-SMA), fibroblast specific protein-1 (FSP-1), and vimentin, and downregulation of endothelial cell-specific markers such as CD31 and vascular endothelial (VE)-cadherin. Furthermore, compared with low-density lipoprotein (LDL), oxidized low-density lipoprotein (ox-LDL) significantly augmented radiation-induced EndMT in HAoEC. These fibrotic phenotypes of ECs were found in atherosclerotic tissues of irradiated ApoE^−/− mice with increased levels of ox-LDL.

Conclusions: Taken together, these observations suggest that ox-LDL accelerates radiation-induced EndMT and subsequently contributes to radiation-induced atherosclerosis, providing a novel target for the prevention of radiation-induced atherosclerosis.

Keywords::

• Atherosclerosis
• radiation
• endothelial- to-mesenchymal transition (EndMT)
• oxidized low-density lipoprotein (ox-LDL)

Acknowledgements

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Declaration of interest

The authors report no conflicts of interest. The authors are responsible for the content and writing of the paper.

This work was supported by the Nuclear Research and Development Program (Grant No. 2011-0031697 and 2012 M2A2A7012483) and the Basic Science Research Program (Grant No. 2012-0002317) through the National Research Foundation (NRF) funded by the Ministry of Education, Science, and Technology of Korea.