Involvement of inducible nitric oxide synthase in radiation-induced vascular endothelial damage

• Published in: Journal of radiation research 2013-11, Vol.54 (6), p.1036-1042
• Main Authors: Hong, Chang-Won, Kim, Young-Mee, Pyo, Hongryull, Lee, Joon-Ho, Kim, Suwan, Lee, Sunyoung, Noh, Jae Myoung
• Format: Article
• Language: English
• Subjects: Acetylcholine; Analysis; Animals; Attenuation; Biology; Blood Flow Velocity - physiology; Blood Flow Velocity - radiation effects; Carotid arteries; Carotid Arteries - physiology; Carotid Arteries - radiation effects; Cells, Cultured; Damage; Dose-Response Relationship, Radiation; Endothelial Cells - physiology; Endothelial Cells - radiation effects; Endothelium; Endothelium-derived relaxing factors; Humans; In Vitro Techniques; Inhibitors; Ionizing radiation; Irradiation; Male; Nitric oxide; Nitric Oxide Synthase Type II - metabolism; Rabbits; Radiation Dosage; Radiotherapy; Stresses; Vasodilation; Vasodilation - physiology; Vasodilation - radiation effects; X-Rays
• ISSN: 0449-3060; 1349-9157
• DOI: 10.1093/jrr/rrt066

The use of radiation therapy has been linked to an increased risk of cardiovascular disease. To understand the mechanisms underlying radiation-induced vascular dysfunction, we employed two models. First, we examined the effect of X-ray irradiation on vasodilation in rabbit carotid arteries. Carotid arterial rings were irradiated with 8 or 16 Gy using in vivo and ex vivo methods. We measured the effect of acetylcholine-induced relaxation after phenylephrine-induced contraction on the rings. In irradiated carotid arteries, vasodilation was significantly attenuated by both irradiation methods. The relaxation response was completely blocked by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a potent inhibitor of soluble guanylate cyclase. Residual relaxation persisted after treatment with L-N-nitroarginine (L-NA), a non-specific inhibitor of nitric oxide synthase (NOS), but disappeared following the addition of aminoguanidine (AG), a selective inhibitor of inducible NOS (iNOS). The relaxation response was also affected by tetraethylammonium, an inhibitor of endothelium-derived hyperpolarizing factor activity. In the second model, we investigated the biochemical events of nitrosative stress in human umbilical-vein endothelial cells (HUVECs). We measured iNOS and nitrotyrosine expression in HUVECs exposed to a dose of 4 Gy. The expression of iNOS and nitrotyrosine was greater in irradiated HUVECs than in untreated controls. Pretreatment with AG, L-N6-(1-iminoethyl) lysine hydrochloride (a selective inhibitor of iNOS), and L-NA attenuated nitrosative stress. While a selective target of radiation-induced vascular endothelial damage was not definitely determined, these results suggest that NO generated from iNOS could contribute to vasorelaxation. These studies highlight a potential role of iNOS inhibitors in ameliorating radiation-induced vascular endothelial damage.