Abstract
The etiology of radiation-induced cardiovascular disease (CVD) after chronic exposure to low doses of ionizing radiation is only marginally understood. We have previously shown that a chronic low-dose rate exposure (4.1 mGy/h) causes human umbilical vein endothelial cells (HUVECs) to prematurely senesce. We now show that a dose rate of 2.4 mGy/h is also able to trigger premature senescence in HUVECs, primarily indicated by a loss of growth potential and the appearance of the senescence-associated markers ß-galactosidase (SA-ß-gal) and p21. In contrast, a lower dose rate of 1.4 mGy/h was not sufficient to inhibit cellular growth or increase SA-ß-gal-staining despite an increased expression of p21. We used reverse phase protein arrays and triplex Isotope Coded Protein Labeling with LC-ESI-MS/MS to study the proteomic changes associated with chronic radiation-induced senescence. Both technologies identified inactivation of the PI3K/Akt/mTOR pathway accompanying premature senescence. In addition, expression of proteins involved in cytoskeletal structure and EIF2 signaling was reduced. Age-related diseases such as CVD have been previously associated with increased endothelial cell senescence. We postulate that a similar endothelial aging may contribute to the increased rate of CVD seen in populations chronically exposed to low-dose-rate radiation.
Highlights
Cardiovascular disease (CVD) – pathologies of the heart, blood vessels and the vascular system of the brain– is the leading cause of morbidity and mortality in the Western world [1] and accounts for nearly one-third of deaths worldwide [2]
The number of cumulative population doublings (CPD) was measured for control and 60.4 CPD (Fig. 2A) and the corresponding value for cells exposed to a dose rate of 2.4 mGy/h was 1160.6, indicating an overall 50% decrease in the growth rate
human umbilical vein endothelial cells (HUVECs) exposed to the 1.4 mGy/h dose rate showed no increase in the number of stained cells compared to control
Summary
Cardiovascular disease (CVD) – pathologies of the heart, blood vessels and the vascular system of the brain– is the leading cause of morbidity and mortality in the Western world [1] and accounts for nearly one-third of deaths worldwide [2]. In the cohort of Mayak nuclear facility workers much of the evidence for an increased risk for ischemic heart disease arose from workers with cumulative external doses greater than 1 Gy, the data are consistent with a linear dose response curve. In this cohort, the individual external gamma-ray doses ranged from below 100 mGy to more than 5 Gy [4]. A study amongst the U.S nuclear power industry workers indicated a strong positive and statistically significant association between radiation dose and mortality from atherosclerotic heart disease, the mean dose being as low as 30 mGy [7]. The recent epidemiological data indicate a residual risk at lower cumulative doses and dose rates than previously estimated, challenging radiation protection authorities to provide more precise risk estimates for CVD at chronic exposures
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