Jung O, Schreiber J G, Geiger H, Pedrazzini T, Busse R, Brandes R P
Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany.
Circulation. 2004 Apr 13;109(14):1795-801. doi: 10.1161/01.CIR.0000124223.00113.A4. Epub 2004 Mar 22.
Isoforms of the NADPH oxidase contribute to vascular superoxide anion (*O2-) formation and limit NO bioavailability. We hypothesized that the endothelial gp91phox-containing NADPH oxidase is predominant in generating the O2- to scavenge endothelial NO and thus is responsible for the development of endothelial dysfunction.
Endothelial dysfunction was studied in aortic rings from wild-type (WT) and gp91phox-knockout (gp91phox-/-) mice with and without renovascular hypertension induced by renal artery clipping (2K1C). Hypertension induced by 2K1C was more severe in WT than in gp91phox-/- mice (158+/-2 versus 149+/-2 mm Hg; P<0.05). Endothelium-dependent relaxation to acetylcholine (ACh) was attenuated in rings from clipped WT but not from clipped gp91phox-/- mice. The reactive oxygen species (ROS) scavenger Tiron, PEG-superoxide dismutase, and the NADPH oxidase inhibitory peptide gp91ds-tat enhanced ACh-induced relaxation in aortae of clipped WT mice. Inhibition of protein kinase C, Rac, and the epidermal growth factor receptor kinase, elements involved in the activation of the NADPH oxidase, restored normal endothelium-dependent relaxation in vessels from clipped WT mice but had no effect on relaxations in those from gp91phox-/- mice. Relaxations to exogenous NO were attenuated in vessels from clipped WT but not clipped gp91phox-/- mice. After removal of the endothelium or treatment with PEG-superoxide dismutase, NO-induced relaxations were identical in vessels from clipped and sham-operated WT and gp91phox mice.
These data indicate that the formation of O2- by the endothelial gp91phox-containing NADPH oxidase accounts for the reduced NO bioavailability in the 2K1C model and contributes to the development of renovascular hypertension and endothelial dysfunction.
NADPH氧化酶的亚型参与血管超氧阴离子（*O2-）的形成并限制一氧化氮（NO）的生物利用度。我们推测，含内皮gp91phox的NADPH氧化酶在生成O2-以清除内皮NO方面起主要作用，因此是内皮功能障碍发生的原因。
在野生型（WT）和gp91phox基因敲除（gp91phox-/-）小鼠的主动脉环中研究内皮功能障碍，这些小鼠有或没有因肾动脉夹闭（2K1C）诱导的肾血管性高血压。2K1C诱导的高血压在WT小鼠中比在gp91phox-/-小鼠中更严重（158±2对149±2 mmHg；P<0.05）。夹闭的WT小鼠主动脉环中对乙酰胆碱（ACh）的内皮依赖性舒张减弱，但夹闭的gp91phox-/-小鼠主动脉环中未减弱。活性氧（ROS）清除剂钛铁试剂、聚乙二醇超氧化物歧化酶和NADPH氧化酶抑制肽gp91ds-tat增强了夹闭的WT小鼠主动脉中ACh诱导的舒张。抑制蛋白激酶C、Rac和表皮生长因子受体激酶（参与NADPH氧化酶激活的元件）可恢复夹闭的WT小鼠血管中正常的内皮依赖性舒张，但对gp91phox-/-小鼠血管的舒张无影响。夹闭的WT小鼠血管中对外源性NO的舒张减弱，但夹闭的gp91phox-/-小鼠血管中未减弱。去除内皮或用聚乙二醇超氧化物歧化酶处理后，夹闭和假手术的WT及gp91phox小鼠血管中NO诱导的舒张相同。
这些数据表明，含内皮gp91phox的NADPH氧化酶生成O2-导致2K1C模型中NO生物利用度降低，并促进肾血管性高血压和内皮功能障碍的发生。
