Ionizing radiation may cause cardiotoxicity not only at high, but even at low (considered as harmless) doses, yet the molecular mechanisms of the heart’s response to low doses are not clear. In this work, we used high-resolution nuclear magnetic resonance (NMR) spectroscopy to detect the early and late effects of radiation on the metabolism of murine hearts. The hearts of C57Bl/6NCrl female mice were irradiated in vivo with single 0.2 Gy or 2 Gy doses using 6 MV photons, then tissues were collected 48 h and 20 weeks after exposure. The most distinct changes in the profile of polar metabolites were detected 48 h after irradiation with 2 Gy, and included increased levels of pantothenate and glutamate as well as decreased levels of alanine, malonate, acetylcarnitine, glycine and adenosine. Significant effects of the 2 Gy dose were also observed 20 weeks after irradiation and included decreased levels of glutamine and acetylcarnitine when compared with age-matched controls. Moreover, several differences were observed between hearts irradiated with 2 Gy and analyzed either 48 h or 20 weeks after the exposure, which included changes in levels of acetylcarnitine, alanine, glycine, glutamate, glutamine, formate, myo-inositol and trimethylamine. No statistically significant effects induced by the 0.2 Gy dose were observed 20 weeks after irradiation. In general, radiation-affected compounds were associated with energy metabolism, fatty acid beta-oxidation, oxidative stress and damage to cell structures. At the same time, radiation-related effects were not detected at the level of tissue histology, which indicated a higher sensitivity of metabolomics-based tests for cardiac tissue response to radiation.

Several lines of evidence indicate that exposure of heart to ionizing radiation increases the risk of cardiotoxicity manifested by heart dysfunction and cardiovascular diseases. It was initially believed that the heart is an organ relatively resistant to radiation. Currently, however, it is suspected that even low doses of radiation (< 2 Gy) may have a negative impact on the cardiovascular system. Cardiotoxicity of ionizing radiation is associated with metabolic changes observed in cardiac cells injured by radiation. In this study we used human cardiomyocytes as a model system, and studied their metabolic response to radiation using high resolution magic angle spinning nuclear magnetic resonance techniques (HR MAS NMR). Cultured in vitro human cardiomyocytes were exposed to ionizing radiation and their survival was assessed by clonogenic assay. Changes in apoptosis intensity and cell cycle distribution after irradiation were measured as well. NMR spectra of cardiomyocytes were acquired using Bruker Avance 400 MHz spectrometer at a spinning rate of 3200 Hz. Survival of cardiomyocytes after NMR experiments was assessed by the Trypan blue exclusion assay. Exposure of cardiomyocytes to small doses of ionizing radiation had no effect on cell proliferation potential and intensity of cell death. However, analysis of metabolic profiles revealed changes in lipids, threonine, glycine, choline, valine, isoleucine, glutamate, reduced glutathione and taurine metabolism. The results of this study show that ionizing radiation affects metabolic profiles of cardiomyocytes even at low doses, which potentially have no effect on cell viability.

Purpose: Ionizing radiation is a risk factor to the whole organism, including the heart. Cardiac damage is considered to be a late effect of radiation exposure. While the acute cardiotoxicity of high doses is well characterized, the knowledge about nature and magnitude of the cardiac risk following lower doses exposure is incomplete. It has been shown that the cardiotoxic effects of radiation are source-, dose- and time-dependent. This paper provides an overview on these dependencies with regard to the molecular responses at the cellular and tissue levels. Main focus is put on the Nuclear Magnetic Resonance (NMR)-based and Mass Spectrometry (MS)-based metabolomic approaches in search of toxicity markers of relatively small doses of radiation. Conclusions: Available literature indicates that radiation exposure affects metabolites associated with: energy production, degradation of proteins and cell membranes, expression of proteins and stress response. Such effects are common for both animal and human studies. However, the specific metabolic response depends on several factors, including the examined organ. Radiation metabolomics can be used to explain the mechanisms of development of radiation-induced heart disease and to find an organ-specific biomarker of radiation exposure. The main aim of this review was to collect the information on the human cardiotoxicity biomarkers. In addition it also summarizes results of the studies on the metabolic responses to ionizing radiation for other organs, as well as the comparative data concerning animal studies.

Resveratrol, a plant-derived polyphenol, is an intensively studied compound with widely documented positive effects on health. Antioxidant activity is the property most often mentioned as responsible for its beneficial effects. Therefore, since the adverse effect of ionizing radiation is primarily related to the induction of oxidative stress, the question arises of whether the use of resveratrol could have a radioprotective effect. This paper summarizes the data on the cytoprotective activity of resveratrol and pieces of evidence for the potential interplay between response to radiation and resveratrol activity. The paper focuses on changes in the metabolic profile of cells and organisms induced by ionizing radiation and exposure to resveratrol. The comparison of metabolic changes induced by both factors provides a rationale for the potential mechanism of the radioprotective effects of resveratrol.

We aimed to evaluate whether resveratrol affects radiation-induced changes in metabolite profiles of the mouse heart. Hearts were irradiated in vivo with a single 2 Gy dose during the resveratrol administration and metabolite profiles of heart tissue were analyzed by the untargeted HR-MAS NMR approach twenty weeks after irradiation. The administration of resveratrol mitigated the radiation-induced decline in the content of choline-containing compounds and unsaturated lipids, which might reflect the stabilization of cell membrane structure against radiation-related damage. Results obtained with this mouse model suggest that the resveratrol supplementation may prevent metabolic changes related to radiation-induced damage in the heart.