In vivo gene transfer of inducible nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits.
In vivo gene transfer of inducible nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits.
复制标题
诱导型一氧化氮合酶体内基因转移至高胆固醇血症兔的颈动脉。
DOI：
10.1161/01.str.0000068366.00173.e7
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发表时间：
2003
期刊：
影响因子：
8.3
通讯作者：
O'Brien,Timothy
中科院分区：
文献类型：
--
作者：
Zanetti,Michela;d'Uscio,LiviusV;Kovesdi,Imre;Katusic,ZvonimirS;O'Brien,Timothy
背景和目的-高胆固醇血症与内皮功能障碍有关。诱导型一氧化氮合酶（iNOS）在动脉粥样硬化血管中上调。然而，其在调节血管功能中的作用尚未完全了解。我们研究了腺病毒介导的iNOS基因转移到高胆固醇血症的兔颈动脉invivo.Methods-Rabbits的效果喂高胆固醇或饲料饮食10周。将两种剂量（1× 108和1× 109空斑形成单位[pfu]/mL）的编码iNOS（AdiNOS）或β-半乳糖苷酶（Adβgal）的腺病毒载体经管腔递送至饲料和胆固醇喂养的动物的颈动脉。血管反应性和超氧化物水平进行了评估，在Adβgal和AdiNOS转导的血管从饲料和胆固醇喂养的动物3 days. Results-Endothelin依赖性血管舒张受损的颈动脉从胆固醇喂养的动物。在AdiNOS转导的动脉中，通过内皮中的阳性免疫染色证明转基因表达。低剂量（1× 108 pfu/mL）AdiNOS转导不影响饲料和胆固醇喂养动物动脉的血管反应性。相反，高剂量（1× 109 pfu/mL）AdiNOS显著降低胆固醇喂养兔血管内皮依赖性舒张，但不降低饲料喂养兔血管内皮依赖性舒张。低剂量和高剂量iNOS基因转移后，高胆固醇喂养动物颈动脉中O2·−水平显著升高（P<0.05）。孵育与O2·−清除剂没有扭转血管功能障碍，在这些artery. Conclusions-Adenoviral介导的过度表达的iNOS的结果在增加生产的O2·−在颈动脉胆固醇，但不是chow-fed动物。高剂量AdiNOS基因转移与胆固醇喂养动物血管内皮依赖性和非依赖性舒张功能降低相关。
Background and Purpose—Hypercholesterolemia is associated with endothelial dysfunction. Inducible nitric oxide synthase (iNOS) is upregulated in atherosclerotic vessels. However, its role in the regulation of vascular function is not completely understood. We examined the effect of adenovirus-mediated gene transfer of iNOS to the hypercholesterolemic rabbit carotid artery in vivo.Methods—Rabbits were fed a high-cholesterol or chow diet for 10 weeks. Two doses (1×108and 1×109plaque-forming units [pfu]/mL) of adenoviral vectors encoding iNOS (AdiNOS) or β-galactosidase (Adβgal) were luminally delivered to the carotid arteries from chow- and cholesterol-fed animals. Vascular reactivity and superoxide levels were assessed in Adβgal- and AdiNOS-transduced vessels from chow- and cholesterol-fed animals after 3 days.Results—Endothelium-dependent vasorelaxation was impaired in the carotid artery from cholesterol-fed animals. In AdiNOS-transduced arteries, transgene expression was demonstrated by positive immunostaining in the endothelium. Transduction with low-dose (1×108pfu/mL) AdiNOS did not affect vascular reactivity in arteries from chow- and cholesterol-fed animals. In contrast, high-dose (1×109pfu/mL) AdiNOS significantly reduced endothelium-dependent relaxation in vessels from cholesterol- but not chow-fed rabbits. After both low- and high-dose iNOS gene transfer, levels of O2·−were significantly (P<0.05) elevated in carotid arteries from cholesterol-fed animals. Incubation with an O2·−scavenger did not reverse vascular dysfunction in these arteries.Conclusions—Adenoviral-mediated overexpression of iNOS results in increased production of O2·−in carotid arteries from cholesterol- but not chow-fed animals. High-dose AdiNOS gene transfer is associated with reduced endothelium-dependent and -independent relaxation in vessels from cholesterol-fed animals.