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Single exposure gamma-irradiation amplifies xanthine oxidase activity and induces endothelial dysfunction in rat aorta

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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 irradiation-initiated upregulation of xanthine oxidase (XO), a primary source of cardiovascular reactive oxygen species, contributes to endothelial dysfunction and increased vascular stiffness. Twenty-two, 3-month-old Sprague–Dawley male rats were gamma-irradiated 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. Endothelial-dependent 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 1-day post-exposure, rats exhibited a significant increase in PWV from pre-exposure. 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 pre-exposure PWV, with sham showing no change over 2 weeks. Thus, these findings suggest that early upregulation of XO contributes to oxidative stress and endothelial nitro-redox imbalance with resultant endothelial dysfunction and altered vascular mechanics. Furthermore, these data identify XO as a potential molecular target for attenuating irradiation-induced cardiovascular injury.

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Acknowledgments

We 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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Authors and Affiliations

  1. Biomedical Engineering, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Kevin G. Soucy, Artin A. Shoukas & Dan E. Berkowitz

  2. Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Tower 711, Baltimore, MD, 21287, USA

    Hyun Kyo Lim, Alexandre Benjo, Lakshmi Santhanam, Sungwoo Ryoo & Dan E. Berkowitz

  3. Wonju College of Medicine, Yonsei University, Wonju, Korea

    Hyun Kyo Lim

  4. Division of Radiation Biology, Medical Department, Brookhaven National Laboratories, Upton, NY, USA

    Marcelo E. Vazquez

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  1. Kevin G. Soucy
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  2. Hyun Kyo Lim
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  3. Alexandre Benjo
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  8. Dan E. Berkowitz
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Correspondence to Dan E. Berkowitz.

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Soucy, K.G., Lim, H.K., Benjo, A. et al. Single exposure gamma-irradiation amplifies xanthine oxidase activity and induces endothelial dysfunction in rat aorta. Radiat Environ Biophys 46, 179–186 (2007). https://doi.org/10.1007/s00411-006-0090-z

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  • DOI: https://doi.org/10.1007/s00411-006-0090-z

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