p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats
p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats
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DOI：
10.1161/01.res.80.1.45
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发表时间：
1997-01-01
影响因子：
20.1
通讯作者：
Griendling, KK
中科院分区：
文献类型：
--
作者：
Fukui, T;Ishizaka, N;Griendling, KK
最近的研究表明，NADPH/NADH氧化酶产生的超氧化物可能参与平滑肌细胞的生长和高血压的发病机制。我们以前表明，血管紧张素II（Ang II）激活p22 phox为基础的NADPH/NADH氧化酶在培养的大鼠血管平滑肌细胞和动物高血压的血管紧张素II输注。为了研究负责这种增加氧化酶活性的机制，我们研究了p22 phox mRNA表达的大鼠高血压植入一个渗透微型泵，提供血管紧张素II（0.7毫克/公斤每天）。血压在开始输注Ang II后3天开始升高，并保持升高长达14天。主动脉p22 phox mRNA表达在术后3天也增加，术后5天增加最多，为假手术组的338 ± 41%。mRNA表达的增加伴随着相应细胞色素含量（两倍）和NADPH氧化酶活性的增加（泵植入后5天假手术大鼠的179+/-11%）。用抗高血压药物氯沙坦（25 mg/kg/天）或肼苯哒嗪（15 mg/kg/天）治疗可抑制mRNA水平和活性的上调。此外，输注重组肝素结合超氧化物歧化酶降低血压和p22 phox mRNA的表达。主动脉组织的原位杂交显示，p22 phox mRNA表达于中膜平滑肌以及在外膜。这些结果表明，血管紧张素II诱导的高血压激活NADPH/NADH氧化酶系统，通过上调该氧化酶系统的一个或几个组件，包括p22 phox的mRNA水平，NADPH/NADH氧化酶系统与高血压的病理在体内。
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 p22phox-based 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.