Exposure to ionizing radiation is a health risk to astronauts, especially on long-duration spaceflight missions. Potential side effects include atherosclerosis and the accelerated aging of blood vessels. The lining of blood vessels, known as the endothelium, is especially sensitive to radiation. This project addresses the hypotheses that radiation will increase endothelial cell damage, decrease the ability for endothelial cells to repair themselves and increase endothelial cell aging. Dr. Artin A. Shoukas and colleagues will test two countermeasures, oxypurinol and statins (the class of drugs that lowers the level of cholesterol), to determine their ability to lessen the adverse effects of radiation-related endothelial dysfunction.
Radiation, Endothelial Cell Senescence, Accelerated Aging and Atherosclerosis
Dan E. Berkowitz, M.D.
Johns Hopkins University School of Medicine
Radiation is known to induce cellular oxidative stress as well as suppress bone marrow proliferation. Data from our lab suggest that gamma and heavy iron ion radiation results in the activation of the reactive oxygen species (ROS) producing enzyme xanthine oxidase (XO). Activation of enzymes, such as arginase, results in a decrease in endothelial protective nitric oxide (NO) with altered nitroso-redox balance and endothelial damage. We hypothesize that radiation will result in activation of ROS-producing enzymes that will result in increased oxidative stress, nitroso-redox imbalance and endothelial cell damage.
We also hypothesize that radiation will decrease endothelial repair mechanism by reducing bone marrow derived endothelial progenitor cells (EPCs). Additionally, we hypothesize that radiation will accelerate endothelial cell senescence by decreasing telomerase activity and increasing the rate of telomere attrition. This will ultimately result in significant endothelial dysfunction, mimic the aging phenotype and accelerate the development of atherosclerosis.
We will test the countermeasure hypothesis that the XO inhibitor (oxypurinol) will reduce radiation-related endothelial dysfunction, that arginase inhibition (which reciprocally regulates nitric oxide synthase) will restore nitroso-redox balance and promote endothelial cell protection. We will also test the hypothesis that statins (endothelial cell protectants through a number of pleotropic effects independent of their lipid-lowering effects) will prevent oxidative stress, improve nitroso-redox imbalance, enhance endothelial progenitor cell production, and prevent telomere decay. In this way, the adverse effects of radiation on the endothelial cell will be attenuated.
In previous years, we have demonstrated that radiation-induced endothelial dysfunction is largely due to the activation of xanthine oxidase in rat aorta as reactive oxygen species derived from xanthine oxidase contribute to impaired endothelial nitric oxide production and attenuated endothelial-dependent vasorelaxation. In the future, we hope to investigate further mechanisms contributing to vascular radiation injury through the use of knockout mouse models. Therefore, during the past year we have begun to characterize the vascular response to radiation of mice. In addition, we are interested in intrinsic endothelial defense mechanisms, and whether these mechanisms are dysregulated by radiation.
Currently, are investigating the role of endothelial progenitor cells (EPCs) in vascular repair after low-dose ionizing radiation (IR) injury. Previous studies have suggested that locally applied low-dose IR is angiogenic. Epidemiological studies and studies from our lab, however, demonstrate that whole body IR exposure is anti-angiogenic and promotes endothelial dysfunction. We hypothesize that the discrepancy between the effects of local and total body irradiation is due to the degree of intact EPC function, where with local exposure, function is intact, compared with total body exposure, where EPC function is most likely compromised. We are investigating the effects of low-dose heavy ion radiation on EPC function and vascular repair using probabilistic and animal models.