Prolonged alterations of cardiomyocyte gene expression following low dose high charge and energy particle radiation--implications for future deep space travel
Schwab, John H.
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INTRODUCTION: Space exploration is ultra-hazardous and unpredictably dangerous. One area of significant concern is the exposure of astronauts to deep space radiation and the development of deleterious health effects. Earth's magnetic field and atmosphere both act to deflect the majority of deep space radiation, protecting humans on the surface of earth as well as astronauts in low Earth orbit missions. Because this type of radiation is not encountered terrestrially, very limited evidence exists in regards to the effects on the well-being. Deep space radiation, which consists of high charge and energy (HZE) particles, may be experimentally reproduced for studies using a particle accelerator. The long-term degenerative effects of cosmic irradiation on the cardiovascular system are vastly unknown. Detailing the molecular response within cardiomyocytes after exposure to HZE irradiation will provide needed knowledge for scientists to accurately assess the cardiovascular risks associated with deep space radiation exposure. OBJECTIVE: The primary objective of this study is to characterize the molecular alterations of gene expression within murine cardiomyocytes following exposure to two different types of HZE. METHODS: Wild type C57B1/6NT (Taconic) mice were exposed to either 90 cGy, 1 GeV proton (1H) or 15 cGy, 1 GeV/nucleon iron (56Fe) HZE particle-radiation. Radiation exposure was performed at the NASA Space Radiation Laboratory located at the Brookhaven National Laboratory (Upton, NY). Biological samples were taken and transcriptome profiling was performed at various time points following irradiation (1, 3, 7, 14, and 28 days). RESULTS: Samples exposed to 56Fe-IR displayed significant levels of gene modulation, while proton-irradiation failed to elicit significant alterations in cardiomyocyte gene transcription compared to sham-irradiated samples. Network pathway analysis of iron-irradiated samples identified multiple biological pathways being significantly modulated. These biological pathways included cell death and survival, free radical scavenging, and inflammatory processes. Multiple points of upstream transcription regulation were identified as key nodes for regulating downstream expression. Validation of the signal transduction network by protein analysis showed that particle-IR clearly regulates a long lived signaling mechanism for p38 MAPK signaling and NFATc4 activation. Electrophoresis mobility shift assays supported the role of transcription factors GATA-4, STAT-3 and NF-𝜅B as key regulators. CONCLUSIONS: The molecular response to 56Fe-IR is unique and induces long-term modulations of gene expression in cardiomyocytes that last up to at least 28 days following radiation exposure. However, exposure to 1H-IR failed to elicit significantly robust alterations in gene expression in cardiomyocytes. Additionally, proteins involved in signal transduction and transcriptional activation via DNA binding play a significant role in the molecular response following HZE particle radiation. This study may have multiple implications for NASA's efforts to develop cardio-degenerative risk estimates for astronauts participating in future deep space missions. By identifying molecular mechanisms and potential molecular markers, scientists can begin to assess excess relative risks and develop strategies to mitigate risks of developing physiological changes which may compromise future missions. This study may also have major safety implications for the increasing number of patients receiving conventional and particle radiotherapy.