No abstract

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 (1H; 0.5 Gy, 1 GeV) and iron ion (56Fe; 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 56Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, 56Fe 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.

Deep-space travel presents risks of exposure to ionizing radiation composed of a spectrum of low-fluence protons (H) and high-charge and energy (HZE) iron nuclei (e.g., Fe). When exposed to galactic cosmic rays, each cell in the body may be traversed byH every 3-4 days and HZE nuclei every 3-4 months. The effects of low-dose sequential fractionated H 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 cGyH every other day (H × 3); group 3, three fractionated doses of 17 cGy H every other day followed by a single low dose of 15 cGyFe two days after the final H dose (H × 3 + Fe); and group 4, a single low dose of 15 cGyFe followed (after 2 days) by three fractionated doses of 17 cGy H every other day (Fe + H × 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.

Background: Ionizing radiation can induce DNA damage in nonirradiated (N-IR) cells via nontargeted effects (NTE). Results: TNF-␣ and IL-1␣ mediate NTE in N-IR bone marrow-derived EPCs, and neutralizing TNF-␣ diminishes NTE in WT and p55 knock-out BM-EPCs. Conclusion: TNF-TNFR2/p75 signaling alters accumulation of inflammatory cytokines that attenuate NTE in N-IR EPCs. Significance: TNFR2/p75 may represent a gene target for mitigation of delayed RBR in BM-EPCs.

It is unknown whether loss of skeletal muscle mass and function experienced by astronauts during space flight could be augmented by ionizing radiation (IR), such as low-dose high-charge and energy (HZE) particles or low-dose high-energy proton radiation. In the current study adult mice were irradiated whole-body with either a single dose of 15 cGy of 1 GeV/n 56Fe-particle or with a 90 cGy proton of 1 GeV/n proton particles. Both ionizing radiation types caused alterations in the skeletal muscle cytoplasmic Ca2+ ([Ca2+]i) homeostasis. 56Fe-particle irradiation also caused a reduction of depolarization-evoked Ca2+ release from the sarcoplasmic reticulum (SR). The increase in the [Ca2+]i was detected as early as 24 h after 56Fe-particle irradiation, while effects of proton irradiation were only evident at 72 h. In both instances [Ca2+]i returned to baseline at day 7 after irradiation. All 56Fe-particle irradiated samples revealed a significant number of centrally localized nuclei, a histologic manifestation of regenerating muscle, 7 days after irradiation. Neither unirradiated control or proton-irradiated samples exhibited such a phenotype. Protein analysis revealed significant increase in the phosphorylation of Akt, Erk1/2 and rpS6k on day 7 in 56Fe-particle irradiated skeletal muscle, but not proton or unirradiated skeletal muscle, suggesting activation of pro-survival signaling. Our findings suggest that a single low-dose 56Fe-particle or proton exposure is sufficient to affect Ca2+ homeostasis in skeletal muscle. However, only 56Fe-particle irradiation led to the appearance of central nuclei and activation of pro-survival pathways, suggesting an ongoing muscle damage/recovery process.