Soucy Kevin G, Lim Hyun Kyo, Attarzadeh David O, Santhanam Lakshmi, Kim Jae Hyung, Bhunia Anil K, Sevinc Baris, Ryoo Sungwoo, Vazquez Marcelo E, Nyhan Daniel, Shoukas Artin A, Berkowitz Dan E
Department of Biomedical Engineering, Johns Hopkins Medical Institutions, 600 N. Wolfe St., Tower 711, Baltimore, MD 21287, USA.
J Appl Physiol (1985). 2010 May;108(5):1250-8. doi: 10.1152/japplphysiol.00946.2009. Epub 2010 Feb 18.
Radiation exposure is associated with the development of various cardiovascular diseases. Although irradiation is known to cause elevated oxidant stress and chronic inflammation, both of which are detrimental to vascular function, the molecular mechanisms remain incompletely understood. We previously demonstrated that radiation causes endothelial dysfunction and increased vascular stiffness by xanthine oxidase (XO) activation. In this study, we investigated whether dietary inhibition of XO protects against radiation-induced vascular injury. We exposed 4-mo-old rats to a single dose of 0 or 5 Gy gamma radiation. These rats received normal drinking water or water containing 1 mM oxypurinol, an XO inhibitor. We measured XO activity and superoxide production in rat aorta and demonstrated that both were significantly elevated 2 wk after radiation exposure. However, oxypurinol treatment in irradiated rats prevented aortic XO activation and superoxide elevation. We next investigated endothelial function through fluorescent measurement of nitric oxide (NO) and vascular tension dose responses. Radiation reduced endothelium-dependent NO production in rat aorta. Similarly, endothelium-dependent vasorelaxation in the aorta of irradiated rats was significantly attenuated compared with the control group. Dietary XO inhibition maintained NO production at control levels and prevented the development of endothelial dysfunction. Furthermore, pulse wave velocity, a measure of vascular stiffness, increased by 1 day postirradiation and remained elevated 2 wk after irradiation, despite unchanged blood pressures. In oxypurinol-treated rats, pulse wave velocities remained unchanged from baseline throughout the experiment, signifying preserved vascular health. These findings demonstrate that XO inhibition can offer protection from radiation-induced endothelial dysfunction and cardiovascular complications.
辐射暴露与多种心血管疾病的发生有关。尽管已知辐射会导致氧化应激升高和慢性炎症，这两者均对血管功能有害，但其分子机制仍未完全明确。我们之前证明，辐射通过激活黄嘌呤氧化酶（XO）导致内皮功能障碍和血管僵硬度增加。在本研究中，我们调查了饮食中抑制XO是否能预防辐射诱导的血管损伤。我们将4月龄大鼠暴露于单次0或5 Gy的γ辐射剂量下。这些大鼠饮用正常饮用水或含有1 mM氧嘌呤醇（一种XO抑制剂）的水。我们测量了大鼠主动脉中的XO活性和超氧化物生成，并证明在辐射暴露2周后两者均显著升高。然而，照射大鼠接受氧嘌呤醇治疗可防止主动脉XO激活和超氧化物升高。接下来，我们通过荧光测量一氧化氮（NO）和血管张力剂量反应来研究内皮功能。辐射降低了大鼠主动脉中内皮依赖性NO的生成。同样，与对照组相比，照射大鼠主动脉中的内皮依赖性血管舒张明显减弱。饮食中抑制XO可使NO生成维持在对照水平，并防止内皮功能障碍的发生。此外，脉搏波速度是血管僵硬度的一个指标，照射后1天增加，照射后2周仍保持升高，尽管血压未变。在接受氧嘌呤醇治疗的大鼠中，整个实验过程中脉搏波速度与基线相比保持不变，表明血管健康得以维持。这些发现表明，抑制XO可以保护免受辐射诱导的内皮功能障碍和心血管并发症。
