Low-dose radiation affects cardiac physiology: gene networks and molecular signaling in cardiomyocytes

Abstract

There are 160,000 cancer patients worldwide treated with particle radiotherapy (RT). With the advent of proton, and high (H) charge (Z) and energy (E) HZE ionizing particle RT, the cardiovascular diseases risk estimates are uncertain. In addition, future deep space exploratory-type missions will expose humans to unknown but low doses of particle irradiation (IR). We examined molecular responses using transcriptome profiling in left ventricular murine cardiomyocytes isolated from mice that were exposed to 90 cGy, 1 GeV proton ((1)H) and 15 cGy, 1 GeV/nucleon iron ((56)Fe) over 28 days after exposure. Unsupervised clustering analysis of gene expression segregated samples according to the IR response and time after exposure, with (56)Fe-IR showing the greatest level of gene modulation. (1)H-IR showed little differential transcript modulation. Network analysis categorized the major differentially expressed genes into cell cycle, oxidative responses, and transcriptional regulation functional groups. Transcriptional networks identified key nodes regulating expression. Validation of the signal transduction network by protein analysis and gel shift assay showed that particle IR clearly regulates a long-lived signaling mechanism for ERK1/2, p38 MAPK signaling and identified NFATc4, GATA4, STAT3, and NF-κB as regulators of the response at specific time points. These data suggest that the molecular responses and gene expression to (56)Fe-IR in cardiomyocytes are unique and long-lasting. Our study may have significant implications for the efforts of National Aeronautics and Space Administration to develop heart disease risk estimates for astronauts and for patients receiving conventional and particle RT via identification of specific HZE-IR molecular markers.

A priming dose of protons alters the early cardiac cellular and molecular response to 56 Fe irradiation

“…Our work confirms these earlier findings and demonstrates that the molecular and cellular response of the heart can be modified by a priming dose of protons at lower energy levels (150 MeV) than in the previous report by Yan et al (1 GeV). Interestingly, there were no clear alterations in genome-wide gene expression arrays performed on mouse heart tissues at 7 days after exposure to protons [35]. Hence, at this time is difficult to speculate on possible mechanisms by which low-dose proton exposure may prime the heart to respond differently to a subsequent exposure to heavy ions.…”

Effects of ionizing radiation on the heart

“…These results suggest that proton exposure induced an as of yet unknown response in the heart that provided protection against further charged particle exposure. Proteomics analysis has started to reveal potential signaling pathways induced by low-dose particle irradiation in the heart [109]. …”

NFATC4 Promotes Quiescence and Chemotherapy Resistance in Ovarian Cancer

“…In normal physiologic states, NFATC4 appears to function partly as a general stress response protein, as it serves a protective role in cardiomyocytes in response to radiation 46 , is activated by mechanical stress in the heart 47 and bladder 48 , and serves as a protective factor during hypoxia 49 . NFATC4 may serve as a similar stress regulator in cancer cells to promote survival.…”