Single exposure gammairradiation amplifies xanthi

Authors: Kevin G Soucy Hyun Kyo Lim Alexandre Benjo Lakshmi Santhanam Sungwoo Ryoo Artin A Shoukas Marcelo E Vazquez Dan E Berkowitz

Publish Date: 2007/01/26

Volume: 46, Issue: 2, Pages: 179-186

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Abstract

Irradiation of the heart and vasculature can cause a spectrum of cardiovascular complications including increased risk of myocardial infarction or coronary heart disease Although irradiation is implicated in oxidant stress and chronic inflammation the underlying molecular mechanisms have not been elucidated We tested the hypothesis that irradiationinitiated upregulation of xanthine oxidase XO a primary source of cardiovascular reactive oxygen species contributes to endothelial dysfunction and increased vascular stiffness Twentytwo 3monthold Sprague–Dawley male rats were gammairradiated at the following doses 0 50 160 and 500 cGy Rats exposed to 500 cGy showed a significant increase in endothelial XO expression and a twofold increase in XO activity compared to the 0 cGy controls Endothelial function was investigated ex vivo through vascular tension dose–responses to the endothelial dependent vasodilator acetylcholine Endothelialdependent relaxation in aorta of the 500 cGy exposed rats was significantly attenuated from the control group Remarkably specific inhibition of XO with oxypurinol restored the relaxation response to that of the control Furthermore these ex vivo results are reflected in vivo through alterations in vascular stiffness as measured by pulse wave velocity PWV As early as 1day postexposure rats exhibited a significant increase in PWV from preexposure The PWV of irradiated rats 50 160 and 500 cGy were greater than those of 0 cGy control rats at 1 day 1 and 2 weeks The sham and irradiated rats possessed equivalent preexposure PWV with sham showing no change over 2 weeks Thus these findings suggest that early upregulation of XO contributes to oxidative stress and endothelial nitroredox imbalance with resultant endothelial dysfunction and altered vascular mechanics Furthermore these data identify XO as a potential molecular target for attenuating irradiationinduced cardiovascular injuryWe would like to thank Dr John F DiCello of Johns Hopkins Medical Institutions for lending his experience and services to this study This work was supported by grants from NASA NNH04ZUU005N the National Space Biomedical Research Institute through NASA CA00401 and the National Institutes of Health AG025017

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