Mechanisms of low-dose/low-dose-rate radiation-induced cardiovascular disease

• Project/Area Number: 18K18194
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 63020:Radiation influence-related
• Research Institution: Hiroshima University
• Principal Investigator: Zaharieva Elena 広島大学, 原爆放射線医科学研究所, 研究員 (30766697)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: chronic radiation / low dose/low dose rate / endothelial cells / cardiovascular disease / atherosclerosis / monocyte adhesion / low dose rate radiation / heart disease risk / endothelial dysfunction / chronic inflammation / endothelial senescence / cardio-vascular disease / low dose radiation / inflammatory cytokines / adhesion molecules / radiation

Outline of Final Research Achievements

The purpose of the current project is to advance the assessment of radiation-associated cardiovascular risk at low doses and dose rates, and to elucidate its molecular mechanisms.
Our data imply that the endothelial lining of blood vessels is a critical target of radiation. Following low and moderate dose/dose rate radiation exposure, endothelial cells exhibited pro-inflammatory changes and cellular senescence with acquisition of robust Senescence Associated Secretory Phenotype (SASP). By using an in vitro co-culture method, we provide evidence for focal accumulation of monocytes on the surface of senescent endothelial cells, which was dependent on both the growth arrest and SASP components of the senescence program. In vivo experiments in a mouse model of atherosclerosis also suggest changes in the SASP profile and aortic morphology after irradiation. We propose that senescence-facilitated endothelial-monocyte affinity is an important step in atherosclerosis initiation by radiation.

Academic Significance and Societal Importance of the Research Achievements

心血管疾患（CVD）は、世界的に主要な死因である。これまでの疫学研究から、放射線被曝が、しきい値無し直線的関係でCVDを誘発する可能性が強く示唆されている。福島原発事故後の健康への社会不安を踏まえ、放射線被曝による心血管系への放射線のリスクを評価し、そのメカニズムを解明することは急務であると言える。本研究は、内皮細胞の老化誘導と機能障害が放射線によるアテローム性動脈硬化症の発症の根本的原因である可能性を示唆する実験結果を提供している。本研究成果は、心血管系への放射線リスクを評価し、CVD予防の標的を特定するための将来的な研究の起点となるものと考える。

Research Products

• [Journal Article] Formation of DNA damage foci in human and mouse primary fibroblasts chronically exposed to gamma radiation at 0.1mGy/min (2021)
  • Author(s): Zaharieva Elena, Sasatani Megumi, Matsumoto Ryoga, Kamiya Kenji
  • Journal Title: Radiation Research Volume: in print Pages: 1-15
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The in vivo role of Rev1 in mutagenesis and carcinogenesis (2020)
  • Author(s): Sasatani Megumi、Zaharieva Elena Karamfilova、Kamiya Kenji
  • Journal Title: Genes and Environment Volume: 42 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s41021-020-0148-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Circular RNA circRNF20 promotes breast cancer tumorigenesis and Warburg effect through miR-487a/HIF-1alpha/HK2 (2020)
  • Author(s): Cao L.、Wang M.、Dong Y.、Xu B.、Chen J.、Ding Y.、Qiu S.、Li L.、Zaharieva E.K.、Zhou X.、Xu Y.
  • Journal Title: Cell Death & Disease Volume: 11 Issue: 2 Pages: 1-10
  • DOI: 10.1038/s41419-020-2336-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inflammatory profile dysregulation in nuclear workers occupationally exposed to low-dose gamma radiation (2019)
  • Author(s): Aneva, N., Zaharieva, E., Katsarska, O., Savova, G., Stankova, K., Djounova, J., Boteva, R.
  • Journal Title: J. of Radiation Research Volume: 60 Issue: 6 Pages: 768-779
  • DOI: 10.1093/jrr/rrz059
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serial image changes in ultrasonography after the excision of benign breast lesions by mammotome biopsy system (2019)
  • Author(s): Ding Yu、Cao Lili、Chen Ju、Zaharieva Elena Karamfilova、Xu Yanbin、Li Liang
  • Journal Title: Saudi Journal of Biological Sciences Volume: 26 Issue: 1 Pages: 178-182
  • DOI: 10.1016/j.sjbs.2018.08.016
  • Peer Reviewed
• [Presentation] Investigation of radiation dose rate effect on loss of heterozygosity in mouse F1 hybrid embryonic stem cells (2020)
  • Author(s): Matsui Ako, Sasatani Megumi, Zaharieva Elena, Kamiya Kenji
  • Organizer: The 5th International Symposium of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science
• [Presentation] DNA damage and oxidative stress in primary murine fibroblasts subjected to acute or chronic gamma radiation. (2020)
  • Author(s): Zaharieva, E., Sasatani, M., Kamiya, K.
  • Organizer: The 60th Annual Research Conference of Atomic Bomb Disease
• [Presentation] Effects of dose-rate on the radiation response of primary fibroblasts (2019)
  • Author(s): Zaharieva, E., Sasatani, M., Kamiya, K.
  • Organizer: 16th International Congress of Radiation Research
• [Presentation] Response of primary murine fibroblasts to low-dose-rate versus acute gamma radiation exposures. (2019)
  • Author(s): Zaharieva, E., Sasatani, M., Kamiya, K.
  • Organizer: Joint QST-NIRS Workshop (to advance France-Japan collaboration in Radiation Research)
• [Presentation] Oxidative stress and DNA damage in primary murine fibroblasts subjected to acute or chronic gamma radiation (2018)
  • Author(s): Zaharieva, E., Sasatani, M., Kamiya, K.
  • Organizer: 3rd International Symposium of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science