Browsing by Author "Bishawi, Muath"

There is a scarcity of knowledge regarding the cardiovascular effects of low dose ionizing radiation (IR) such as the one experienced during medical tests, radiation therapy or space travel. This is becoming more of a pressing problem given the enormous increase in radiation exposure by the average American today, and the renewed interest in deep space travel. Multiple epidemiologic studies suggest a higher rate of delayed cardiovascular related morbidity and mortality after low dose acute radiation exposure. These studies are significantly limited by a number of confounders such as cancer comorbidity, poor follow up, and largely estimated radiation doses that might not be accurate. These limitations are also seen in studies on the effect of space radiation on long term cardiovascular mortality and accelerated atherosclerosis. Animal studies have been used to simulate the effect of terrestrial and space radiation scenarios on cardiac function. These studies have led to conflicting conclusions, and had important challenges related to methods of assessment of cardiac injury. Furthermore, available studies to date had limited follow up times, and no study has evaluated the effects of more complex radiation scenarios that are likely to be experienced in space such as Galactic Cosmic Rays (GCRs). Our overall hypothesis is that IR is associated with early damage to healthy cardiomyocytes and vascular cells that eventually leads to long term cardiovascular dysfunction.

In the first part of this work, we hypothesize that IR is associated with a delayed cardiovascular derangement phenotype late after initial exposure. To test this hypothesis, we use a mouse animal model to study the effect of different radiation scenarios on cardiovascular function. Animals were exposed to one of the following (a) Gamma Rays (50-200 cGy), (b) 56Fe (15-50 cGy), (c) 16O (15-50cGy) heavy ions, and (d) 150cGy Galactic Cosmic Rays all using the particle accelerator at Brookhaven National Labs (BNL). They were then followed up for 9-12 months, and underwent cardiac MRI, pressure volume loop assessments, transthoracic echocardiograms and other histological evaluations. These studies revealed that GCR exposed animals had a clinically meaningful decline in their cardiac function, with a significant change in their arterial elastance. These findings were further confirmed on histology with their aortas demonstrating elastic fiber destruction and disorganization.

These animal studies however could not fully differentiate between a primary cardiac injury or a secondary cardiac response to a primary vascular injury to the aorta. Our hypothesis for the second part of this work, was that IR is associated with a unique and differentiated injury to cardiomyocytes that contributes to the previously seen cardiovascular phenotype. We therefore conducted additional experiments on isolated rat ventricular cardiomyocyte in collaboration with the Bursac lab. These studies used both 2D cultured cells, as well as a novel cardiac patch system both exposed to Gamma rays and X-rays (0.1-2 Gy). These cells underwent proteomics analysis, as well as a number of different biological and functional assays. While the acute functional effect of these radiation doses on cardiomyocytes was small, these irradiated cells produced a significant amount of reactive oxygen species and exhibited a large effect of radiation on mitochondrial related proteins, including elements of oxidative phosphorylation. We also noted a number of different pathways involved at different doses of radiation. This was an important finding, given that despite no changes in early cell death, the effect of these important proteomics changes on long term cardiac function maybe important.

Finally, for the last part of this dissertation, our hypothesis was that IR uniquely affects endothelial cells (ECs) and smooth muscle cells (SMCs) by inducing early senescence that is primarily due to over production of mitochondrial specific reactive oxygen species. To test this hypothesis, we use primary coronary artery endothelial cells, primary human aortic endothelial cells and primary coronary artery smooth muscle cells. These relevant cell types were then examined for their response to a single dose of radiation exposure. Given the previous findings of important mitochondria involvement even at low radiation doses, we used a novel mitochondrial specific ROS scavenger, that blocks the release of mROS, mito-TEMPO. Cells treated with mito-TEMPO had a significant decrease in observed cellular senescence an important hallmark indicator of cellular dysfunction. This strategy might have a potential therapeutic role in the prolonged cardiovascular effects of radiation exposure.

In summary, data generated in this dissertation supports the overall hypothesis that IR is associated with long term cardiovascular dysfunction that can be explained by early injury to cardiac, endothelial and smooth muscle cells. Galactic Cosmic Rays appear to significantly effect long term cardiovascular function, which has important implications on deep space travel. This effect is likely multifactorial, involving a number of organs, including the aorta. Cardiomyocytes, despite being resilient to death from radiation as compared to other cells types, appear to undergo a number of proteomics alterations after low dose radiation exposure, with significant involvement of the mitochondrial machinery. Finally, human vascular ECs and SMCs are highly sensitive to radiation exposure, and strategies that target mitochondrial specific ROS production might play an important role in mitigating the long-term vascular effects after radiation exposure.