Nakane H, Miller F J, Faraci F M, Toyoda K, Heistad D D
Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City 52242, USA.
Hypertension. 2000 Feb;35(2):595-601. doi: 10.1161/01.hyp.35.2.595.
Angiotensin II stimulates vascular NADPH oxidase to produce superoxide, which can react with nitric oxide and impair vasomotor function. We tested the hypothesis that the overexpression of endothelial nitric oxide synthase (eNOS) or superoxide dismutase (SOD) would correct angiotensin II-induced endothelial dysfunction. We examined the effects of the gene transfer of eNOS or 2 isoforms of SOD to the aorta in angiotensin II-treated rabbits on vasomotor function. New Zealand White rabbits were treated for 1 week with angiotensin II (100 ng. kg(-1). min(-1)) or saline by osmotic minipumps. In angiotensin II-treated rabbits, mean blood pressure was 107+/-8 mm Hg; it was 67+/-5 mm Hg in saline-infused rabbits (P<0.05). In aortas from angiotensin II-treated rabbits, lucigenin-enhanced chemiluminescence demonstrated a 2.5-fold increase in superoxide levels, and the oxidative fluorescent probe hydroethidine indicated increased superoxide levels throughout the vascular wall, especially in the endothelium and adventitia. Maximal relaxation to acetylcholine was less in aortas from rabbits treated with angiotensin II (72+/-5% versus 87+/-4% in saline-treated rabbits; P<0.01), but responses to sodium nitroprusside were similar. Segments of the thoracic aorta were incubated in vitro with an adenoviral vector that expressed eNOS, copper zinc SOD (CuZnSOD), extracellular SOD (ECSOD), or beta-galactosidase. beta-Gal treatment with adenovirus containing the gene for eNOS (AdeNOS) but not adenovirus containing the gene for beta-gal (Adbeta-gal) (control virus) restored responses to acetylcholine (82+/-3% after AdeNOS and 67+/-4% after Adbeta-gal). Gene transfer of CuZnSOD or ECSOD did not improve the endothelium-dependent relaxation of the aorta in rabbits that received angiotensin II. Thus, gene transfer of eNOS, but not SOD, effectively restores vasomotor function in angiotensin II-infused rabbits.
血管紧张素II刺激血管NADPH氧化酶产生超氧化物，超氧化物可与一氧化氮反应并损害血管舒缩功能。我们检验了如下假设：内皮型一氧化氮合酶（eNOS）或超氧化物歧化酶（SOD）的过表达可纠正血管紧张素II诱导的内皮功能障碍。我们研究了将eNOS或2种SOD同工型基因转移至经血管紧张素II处理的兔主动脉后对血管舒缩功能的影响。新西兰白兔用渗透微型泵给予血管紧张素II（100 ng·kg⁻¹·min⁻¹）或生理盐水处理1周。在经血管紧张素II处理的兔中，平均血压为107±8 mmHg；在输注生理盐水的兔中为67±5 mmHg（P<0.05）。在经血管紧张素II处理的兔的主动脉中，光泽精增强的化学发光显示超氧化物水平增加2.5倍，氧化荧光探针氢乙啶表明整个血管壁超氧化物水平增加，尤其是在内皮和外膜。经血管紧张素II处理的兔的主动脉对乙酰胆碱的最大舒张反应较小（72±5%，而生理盐水处理的兔为87±4%；P<0.01），但对硝普钠的反应相似。将胸主动脉段与表达eNOS、铜锌超氧化物歧化酶（CuZnSOD）、细胞外超氧化物歧化酶（ECSOD）或β-半乳糖苷酶的腺病毒载体在体外孵育。用含eNOS基因的腺病毒（AdeNOS）而非含β-半乳糖苷酶基因的腺病毒（Adβ-gal）（对照病毒）进行β-半乳糖苷酶处理可恢复对乙酰胆碱的反应（AdeNOS处理后为82±3%，Adβ-gal处理后为67±4%）。CuZnSOD或ECSOD的基因转移并未改善接受血管紧张素II的兔主动脉的内皮依赖性舒张。因此，eNOS而非SOD的基因转移可有效恢复输注血管紧张素II的兔的血管舒缩功能。
