Fukui T, Ishizaka N, Rajagopalan S, Laursen J B, Capers Q, Taylor W R, Harrison D G, de Leon H, Wilcox J N, Griendling K K
Department of Medicine, Emory University, Atlanta, Ga 30322, USA.
Circ Res. 1997 Jan;80(1):45-51. doi: 10.1161/01.res.80.1.45.
Recent studies suggest that superoxide production by the NADPH/NADH oxidase may be involved in smooth muscle cell growth and the pathogenesis of hypertension. We previously showed that angiotensin II (Ang II) activates a p22phoxbased NADPH/NADH oxidase in cultured rat vascular smooth muscle cells and in animals made hypertensive by infusion of Ang II. To investigate the mechanism responsible for this increased oxidase activity, we examined p22phox mRNA expression in rats made hypertensive by implanting an osmotic minipump that delivered Ang II (0.7 mg/kg per day). Blood pressure began to increase 3 days after the start of Ang II infusion and remained elevated for up to 14 days. Expression of p22phox mRNA in aorta was also increased after 3 days and reached a maximum increase of 338 +/- 41% by 5 days after pump implantation compared with the value after sham operation. This increase in mRNA expression was accompanied by an increase in the content of the corresponding cytochrome (twofold) and NADPH oxidase activity (179 +/- 11% of that in sham-operated rats 5 days after pump implantation). Treatment with the antihypertensive agents losartan (25 mg/kg per day) or hydralazine (15 mg/kg per day) inhibited this upregulation of mRNA levels and activity. Furthermore, infusion of recombinant heparin-binding superoxide dismutase decreased both blood pressure and p22phox mRNA expression. In situ hybridization of aortic tissue showed that p22phox mRNA was expressed in medial smooth muscle as well as in the adventitia. These findings suggest that Ang II-induced hypertension activates the NADPH/NADH oxidase system by upregulating mRNA levels of one or several components of this oxidase system, including the p22phox, and that the NADPH/NADH oxidase system is associated with the pathology of hypertension in vivo.
近期研究表明，NADPH/NADH氧化酶产生的超氧化物可能参与平滑肌细胞生长及高血压的发病机制。我们之前发现，血管紧张素II（Ang II）可激活培养的大鼠血管平滑肌细胞及通过输注Ang II诱导高血压的动物体内基于p22phox的NADPH/NADH氧化酶。为研究氧化酶活性增加的机制，我们检测了通过植入渗透微型泵输注Ang II（0.7 mg/kg每天）诱导高血压的大鼠中p22phox mRNA的表达。Ang II输注开始3天后血压开始升高，并持续升高长达14天。与假手术组相比，泵植入后3天主动脉中p22phox mRNA的表达也增加，至泵植入后5天最大增加338±41%。mRNA表达的增加伴随着相应细胞色素含量的增加（两倍）及NADPH氧化酶活性的增加（泵植入后5天，为假手术组大鼠的179±11%）。用抗高血压药物氯沙坦（25 mg/kg每天）或肼屈嗪（15 mg/kg每天）治疗可抑制mRNA水平和活性的这种上调。此外，输注重组肝素结合超氧化物歧化酶可降低血压和p22phox mRNA表达。主动脉组织的原位杂交显示，p22phox mRNA在外膜及中膜平滑肌中均有表达。这些发现表明，Ang II诱导的高血压通过上调该氧化酶系统一个或多个组分（包括p22phox）的mRNA水平激活NADPH/NADH氧化酶系统，且NADPH/NADH氧化酶系统与体内高血压的病理过程相关。
