p22phox mRNA Expression and NADPH Oxidase Activity Are Increased in Aortas From Hypertensive Rats

Abstract

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.

Hypercholesterolemic diet induces hepatic steatosis and alterations in mRNA expression of NADPH oxidase in rat livers

“…The p22 PHOX functions as an integral subunit of the final electron transporter from NADPH to heme to molecular oxygen in generating superoxide anion (39). In this study, we found increased expression of p47 PHOX and p22 PHOX subunits of NADPH oxidase in the H group, thus indicating that this increase could be contributing to the activation of this enzyme complex, favoring the generation of ROS.…”

Superoxide as a Messenger of Endothelial Function

“…Thus p22 phox is essential for the activation process of NAD(P)H oxidase. Meanwhile, several other laboratories confirmed the induction of the enzyme in diabetes and also in hypertension (Fukui et al, 1997;Griendling et al, 2000;Hink …”

Reactive oxygen species and vascular biology: implications in human hypertension

“…134,135 OXIDATIVE STRESS AND HUMAN HYPERTENSION Almost all experimental models of hypertension show some form of oxidative excess including genetic forms (spontaneously hypertensive rats, stroke-prone spontaneously hypertensive rats), surgically induced (2K1C, aortic banding), endocrine-induced (Ang II, aldosterone, deoxycorticosterone acetate) and diet-induced hypertension (salt, fat). [21][22][23][136][137][138] Sources of ROS in experimental models include Noxes (Nox1, Nox2 and Nox4), xanthine oxidase, uncoupled nitric oxide synthase and mitochondrial oxidases. Mice deficient in ROSgenerating enzymes have lower blood pressure compared with wild-type counterparts, and Ang II infusion fails to induce hypertension in these mice.…”