HZE⁵⁶Fe-Ion Irradiation Induces Endothelial Dysfunction in Rat Aorta: Role of Xanthine Oxidase

Abstract

Ionizing radiation has been implicated in the development of significant cardiovascular complications. Since radiation exposure is associated with space exploration, astronauts are potentially at increased risk of accelerated cardiovascular disease. This study investigated the effect of high atomic number, high-energy (HZE) iron-ion radiation on vascular and endothelial function as a model of space radiation. Rats were exposed to a single whole-body dose of iron-ion radiation at doses of 0, 0.5 or 1 Gy. In vivo aortic stiffness and ex vivo aortic tension responses were measured 6 and 8 months after exposure as indicators of chronic vascular injury. Rats exposed to 1 Gy iron ions demonstrated significantly increased aortic stiffness, as measured by pulse wave velocity. Aortic rings from irradiated rats exhibited impaired endothelial-dependent relaxation consistent with endothelial dysfunction. Acute xanthine oxidase (XO) inhibition or reactive oxygen species (ROS) scavenging restored endothelial-dependent responses to normal. In addition, XO activity was significantly elevated in rat aorta 4 months after whole-body irradiation. Furthermore, XO inhibition, initiated immediately after radiation exposure and continued until euthanasia, completely inhibited radiation-dependent XO activation. ROS production was elevated after 1 Gy irradiation while production of nitric oxide (NO) was significantly impaired. XO inhibition restored NO and ROS production. Finally, dietary XO inhibition preserved normal endothelial function and vascular stiffness after radiation exposure. These results demonstrate that radiation induced XO-dependent ROS production and nitroso-redox imbalance, leading to chronic vascular dysfunction. As a result, XO is a potential target for radioprotection. Enhancing the understanding of vascular radiation injury could lead to the development of effective methods to ameliorate radiation-induced vascular damage.

Effect of electron radiation on vasomotor function of the left anterior descending coronary artery

“…The fact that the relaxation response was lower in the radiation-treated group suggests that radiation exposure damages the vascular endothelium. This is consistent with previous results demonstrating that aortic endothelial-dependent vasorelaxation was impaired in rats exposed to a single whole body dose of either 0.5 Gy cesium-137 gamma-irradiation [7] or 1 Gy iron-ion irradiation [4]. BK is an endothelium-dependent dilator that acts directly on endothelial cells, causing the release of nitric oxide (NO), PGI2 and perhaps endothelium derived dilating factor(s) [28–30].…”

Radiation Exposure Induces Inflammasome Pathway Activation in Immune Cells

“…This observation suggests that uric acid levels affect cell-mediated immune responses, which supports the idea that inflammasome activation by radiation can suppress immune function by a uric acid dependent mechanism. In addition, it has been reported that blocking xanthine oxidase after radiation protected the vascular endothelium integrity in the aorta of rats (48). This provides evidence that blocking uric acid production after radiation injury might have additional beneficial effects which extend beyond the immune system and may also be mediated by inflammasome-independent mechansims.…”

Biological effects of space radiation and development of effective countermeasures

“…In these studies, it was concluded that 56 Fe ions can promote the progression of atherosclerotic lesions to an advanced stage characterized by compositional changes indicative of increased thrombogenicity and instability. In numerous other studies, space radiation has been shown to have detrimental effects of many other parameters related to cardiovascular and circulatory diseases, with particularly strong effects leading to endothelial dysfunction [e.g., (87)] and angiogenesis [e.g., (88–91)].…”