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Introduction
Cardiovascular disease is considered to be one of the most important non-cancer long-term effects of ionizing radiation, as evidenced by the epidemiological data of atomic bomb survivors exposed to doses of 0.5 to 2 Gy (1). In the context of space exploration, high linear energy transfer (LET) radiation found in space produces high values of relative biological effectiveness (RBE), as compared to low LET radiation, such as X-rays or gamma-rays, which can increase the health risks to astronauts (2). Indeed, during long-term missions, such as a journey to Mars, astronauts are bound to be exposed to cumulative doses between 0.3 and 4 Sv, depending on the spacecraft shielding and on the intensity of solar particle events (3).
Heavy ion irradiation is also used for terrestrial applications, such as non-conventional radiotherapy (hadron therapy), which takes advantage of the depth distribution of the dose, which is maximal at the Bragg peak, and of the increased RBE, allowing the enhanced killing effect on tumor cells while sparing the healthy tissue (4,5). However, little is known of the molecular mechanisms involved in the enhanced killing properties of heavy ion irradiation. Improving our understanding of the effects of heavy ion radiation, particularly on the cardiovascular system that may be irradiated during treatment, is therefore of utmost importance for both long-term space missions and hadron therapy.
Endothelial cells are critical targets in radiation-induced cardiovascular damage (1,6,7). While high doses of low LET radiation induce pro-inflammatory responses in endothelial cells, the opposite has been observed upon exposure to low doses (8–10). The mechanisms involved are not yet fully understood; however, they appear to be at least partly linked to the transcription factor, nuclear factor (NF)-κB, and the nitric oxide signaling pathway, which in turn mediates various cellular responses, including the secretion of cytokines [such as transforming growth factor (TGF)-β1, interleukin (IL)-6, interferon (IFN)-γ, IFN-β and tumor necrosis factor (TNF)-α] and chemokines (9–11). Another possible mechanism of radiation-induced cardiovascular alteration, as shown upon low LET radiation (12–16), is the endothelial retraction and the impairment of cellular adhesion. Matrix metalloproteinases (MMPs), Rho GTPases, calcium signaling and reactive oxygen species seem to be important factors that stimulate modifications in cell junctions and the cytoskeleton through adhesion molecules and actin (12–16). Although high LET radiation...