Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta.
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.
Soucy
Kevin G
KG
Department of Biomedical Engineering, Johns Hopkins Medical Institutions, 600 N. Wolfe St., Tower 711, Baltimore, MD 21287, USA.
Lim
Hyun Kyo
HK
Attarzadeh
David O
DO
Santhanam
Lakshmi
L
Kim
Jae Hyung
JH
Bhunia
Anil K
AK
Sevinc
Baris
B
Ryoo
Sungwoo
S
Vazquez
Marcelo E
ME
Nyhan
Daniel
D
Shoukas
Artin A
AA
Berkowitz
Dan E
DE
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology / Q000528:radiation effects; D004032:Diet; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004548:Elasticity; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005720:Gamma Rays; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010117:Oxypurinol / Q000008:administration & dosage*; D011673:Pulsatile Flow; D011833:Radiation Injuries, Experimental / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D018608:Ultrasonography, Doppler; D014652:Vascular Diseases / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D014664:Vasodilation / Q000187:drug effects / Q000528:radiation effects; D014665:Vasodilator Agents / Q000494:pharmacology; D014916:Whole-Body Irradiation; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D014969:Xanthine Oxidase; D010117:Oxypurinol