P22PHOX MESSENGER-RNA EXPRESSION AND NADPH OXIDASE ACTIVITY ARE INCREASED IN AORTAS FROM HYPERTENSIVE RATS

Recent studies suggest that superoxide production by the NADPH/NADH ox idase may be involved in smooth muscle cell growth and the pathogenesi s of hypertension. We previously showed that angiotensin II (Ang II) a ctivates a p22phox-based NADPH/NADH oxidase in cultured rat vascular s mooth muscle cells and in animals made hypertensive by infusion of Ang II. To investigate the mechanism responsible for this increased oxida se activity, we examined p22phox mRNA expression in rats made hyperten sive by implanting an osmotic minipump that delivered Ang II (0.7 mg/k g 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 o f p22phox mRNA in aorta was also increased after 3 days and reached a maximum increase of 338+/-41% by 5 days after pump implantation compar ed with the value after sham operation. This increase in mRNA expressi on 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 (1 5 mg/kg per day) inhibited this upregulation of mRNA levels and activi ty. Furthermore, infusion of recombinant heparin-binding superoxide di smutase decreased both blood pressure and p22phox mRNA expression. In situ hybridization of aortic tissue showed that p22phox mRNA was expre ssed in medial smooth muscle as well as in the adventitia. These findi ngs suggest that Ang II-induced hypertension activates the NADPH/NADH oxidase system by upregulating mRNA levels of one or several component s of this oxidase system, including the p22phox, and that the NADPH/NA DH oxidase system is associated with the pathology of hypertension in vivo.