LET-Dependent Low Dose and Synergistic Inhibition of Human Angiogenesis by Charged Particles: Validation of miRNAs that Drive Inhibition

Yen-Ruh Wuu; Burong Hu; Hazeem Okunola; Amber M Paul; Elizabeth A Blaber; Margareth Cheng-Campbell; Afshin Beheshti; Peter Grabham

doi:10.1016/j.isci.2020.101771

LET-Dependent Low Dose and Synergistic Inhibition of Human Angiogenesis by Charged Particles: Validation of miRNAs that Drive Inhibition

iScience. 2020 Nov 25;23(12):101771. doi: 10.1016/j.isci.2020.101771. eCollection 2020 Dec 18.

Authors

Yen-Ruh Wuu¹, Burong Hu², Hazeem Okunola³, Amber M Paul^{4

5}, Elizabeth A Blaber^{5

6}, Margareth Cheng-Campbell^{5

6}, Afshin Beheshti⁷, Peter Grabham³

Affiliations

¹ Drexel University College of Medicine, Philadelphia, PA 19129, USA.
² Department of Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
³ Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, VC 11-243, 630 West 168 Street, New York, NY 10032, USA.
⁴ Universities Space Research Association, Columbia, MD 21046, USA.
⁵ Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA.
⁶ Department of Bioengineering, Center for Biotechnology & InterdisciplinaryStudies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
⁷ KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA.

Abstract

Space radiation inhibits angiogenesis by two mechanisms depending on the linear energy transfer (LET). Using human 3D micro-vessel models, blockage of the early motile stage of angiogenesis was determined to occur after exposure to low LET ions (<3 KeV/AMU), whereas inhibition of the later stages occurs after exposure to high LET ions (>8 KeV/AMU). Strikingly, the combined effect is synergistic, detectible as low as 0.06 Gy making mixed ion space radiation more potent. Candidates for bystander transmission are microRNAs (miRNAs), and analysis on miRNA-seq data from irradiated mice shows that angiogenesis would in theory be downregulated. Further analysis of three previously identified miRNAs showed downregulation of their targets associated with angiogenesis and confirmed their involvement in angiogenesis pathways and increased health risks associated with cardiovascular disease. Finally, synthetic molecules (antagomirs) designed to inhibit the predicted miRNAs were successfully used to reverse the inhibition of angiogenesis.

Keywords: Molecular Biology; Radiation Biology; Space Sciences.