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

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.

Different Sequences of Fractionated Low-Dose Proton and Single Iron-Radiation-Induced Divergent Biological Responses in the Heart.

Deep-space travel presents risks of exposure to ionizing radiation composed of a spectrum of low-fluence protons (1H) and high-charge and energy (HZE) iron nuclei (e.g., 56Fe). When exposed to galactic cosmic rays, each cell in the body may be traversed by 1H every 3-4 days and HZE nuclei every 3-4 months. The effects of low-dose sequential fractionated 1H or HZE on the heart are unknown. In this animal model of simulated ionizing radiation, middle-aged (8-9 months old) male C57BL/6NT mice were exposed to radiation as follows: group 1, nonirradiated controls; group 2, three fractionated doses of 17 cGy 1H every other day (1H × 3); group 3, three fractionated doses of 17 cGy 1H every other day followed by a single low dose of 15 cGy 56Fe two days after the final 1H dose (1H × 3 + 56Fe); and group 4, a single low dose of 15 cGy 56Fe followed (after 2 days) by three fractionated doses of 17 cGy 1H every other day (56Fe + 1H × 3). A subgroup of mice from each group underwent myocardial infarction (MI) surgery at 28 days postirradiation. Cardiac structure and function were assessed in all animals at days 7, 14 and 28 after MI surgery was performed. Compared to the control animals, the treatments that groups 2 and 3 received did not induce negative effects on cardiac function or structure. However, compared to all other groups, the animals in group 4, showed depressed left ventricular (LV) functions at 1 month with concomitant enhancement in cardiac fibrosis and induction of cardiac hypertrophy signaling at 3 months. In the irradiated and MI surgery groups compared to the control group, the treatments received by groups 2 and 4 did not induce negative effects at 1 month postirradiation and MI surgery. However, in group 3 after MI surgery, there was a 24% increase in mortality, significant decreases in LV function and a 35% increase in post-infarction size. These changes were associated with significant decreases in the angiogenic and cell survival signaling pathways. These data suggest that fractionated doses of radiation induces cellular and molecular changes that result in depressed heart functions both under basal conditions and particularly after myocardial infarction.

Corrigendum to "Particle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells".

[This corrects the article DOI: 10.1155/2015/496512.].

Particle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells.

Bone-marrow- (BM-) derived endothelial progenitor cells (EPCs) are critical for endothelial cell maintenance and repair. During future space exploration missions astronauts will be exposed to space irradiation (IR) composed of a spectrum of low-fluence protons ((1)H) and high charge and energy (HZE) nuclei (e.g., iron-(56)Fe) for extended time. How the space-type IR affects BM-EPCs is limited. In media transfer experiments in vitro we studied nontargeted effects induced by (1)H- and (56)Fe-IR conditioned medium (CM), which showed significant increase in the number of p-H2AX foci in nonirradiated EPCs between 2 and 24 h. A 2-15-fold increase in the levels of various cytokines and chemokines was observed in both types of IR-CM at 24 h. Ex vivo analysis of BM-EPCs from single, low-dose, full-body (1)H- and (56)Fe-IR mice demonstrated a cyclical (early 5-24 h and delayed 28 days) increase in apoptosis. This early increase in BM-EPC apoptosis may be the effect of direct IR exposure, whereas late increase in apoptosis could be a result of nontargeted effects (NTE) in the cells that were not traversed by IR directly. Identifying the role of specific cytokines responsible for IR-induced NTE and inhibiting such NTE may prevent long-term and cyclical loss of stem and progenitors cells in the BM milieu.

Cardiovascular risks associated with low dose ionizing particle radiation.

Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton ((1)H; 0.5 Gy, 1 GeV) and iron ion ((56)Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in (56)Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, (56)Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.