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
Affiliations
Yen-Ruh Wuu
Drexel University College of Medicine, Philadelphia, PA 19129, USA
Burong Hu
Department of Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
Hazeem Okunola
Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, VC 11-243, 630 West 168th Street, New York, NY 10032, USA
Amber M. Paul
Universities Space Research Association, Columbia, MD 21046, USA; Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
Elizabeth A. Blaber
Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA; Department of Bioengineering, Center for Biotechnology & InterdisciplinaryStudies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Margareth Cheng-Campbell
Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA; Department of Bioengineering, Center for Biotechnology & InterdisciplinaryStudies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Afshin Beheshti
KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA; Corresponding author
Peter Grabham
Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, VC 11-243, 630 West 168th Street, New York, NY 10032, USA; Corresponding author
Summary: 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 (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.
