Role of Tissue Iron in Development of Cardiovascular Delayed Effects of Acute Radiation Exposure

Abstract

The threat of radiation exposure from terrorist activity, warfare, or accidents creates an urgent need to develop agents to mitigate the acute and chronic effects of high dose rate total body irradiation (TBI). High level short‐term radiation exposure results in rapid organ injury leading to development of the acute radiation syndrome (ARS), which if untreated will result in death within weeks. Survivors of ARS will experience the delayed effects of acute radiation exposure (DEARE), which include development of chronic pathology and dysfunction of multiple organ systems months to years following exposure. However, the factors and mechanisms that regulate the onset and progression of cardiovascular DEARE are unclear. The goal of the current study was to determine the possible role for abnormal iron metabolism in the development of cardiac DEARE, especially vascular pathology. Studies utilized the ARS mouse model with gamma radiation exposure at 853 cGy (LD50) and time points from 1 day to 4 months post‐TBI.Serum iron was elevated at 1 day post‐TBI, peaked at 2 weeks, and returned to non‐irradiated control values by 4 weeks post‐TBI. A similar trend was seen for transferrin saturation, and both results correlated inversely with red blood cell number, hematocrit, and hemoglobin concentrations. Perls' Prussian Blue staining was used to detect iron (hemosiderin) deposition in heart paraffin‐embedded tissue sections, and myocardial iron was present as early as 2 weeks post‐TBI. Pretreatment of mice with the iron chelator deferiprone in drinking water decreased myocardial iron deposition (P=0.055), but not serum iron, at 2 weeks. A histological assessment of coronary artery endothelial cell (EC) density showed intimal nuclei per unit area significantly decreased as early as two weeks post‐TBI vs. non‐irradiated controls (P<0.05), and the decrease persisted to 4 months post‐TBI. EC density in deferiprone‐treated mice was significantly increased at 2 and 4 weeks post‐TBI compared to irradiated non‐treated mice (P<0.03). Administration of the ferroptosis inhibitor ferrostatin‐1 via daily i.p. injection for 2 weeks post‐TBI resulted in no change in coronary artery EC density compared to vehicle controls. Taken together, the results suggest the presence of tissue iron contributes to endothelial cell loss occurring early following TBI and is a significant event impacting the development of DEARE. This information may facilitate development of novel medical countermeasures to prevent or mitigate cardiovascular DEARE‐related pathophysiology.Support or Funding InformationNIH 1U01AI107340‐01 (C. Orschell), IUPUI Research Support Funds Grant (S. Miller)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.