Role of NAD(P)H Oxidase and Its Regulation in Chronic Hypertension

Oxidative stress is caused by the overproduction of oxidizing chemicals, which disrupts the balance between oxidizing power and reducing power. Oxidizing power is increased by the production of reactive oxygen species (ROS), including hydrogen peroxide, lipid peroxide, and radicals such as hydroxyl radical, hydroxyperoxyl radical, peroxyradical, nitric oxide, peroxynitrite and superoxide anion. Under physiological conditions, ROS act as a kind of scavenger to break down bacteria or unnecessary molecules. However, they can have undesirable effects when overproduced. Oxidative stress is considered to be involved in various pathological conditions, such as ischemic heart disease, vascular remodeling, nephropathy and brain damage (1–3). Superoxide anion is one of the most important ROS involved in pathogenesis. Production of superoxide anion is facilitated by NAD(P)H oxidase, an enzyme composed of several membrane and intracellular components. The subunit proteins vary depending on the tissue. In the vascular wall, NAD(P)H oxidase consists of membrane components, such as gp91phox homologue (Nox1 and Nox4) and p22phox, and intracellular components, such as p47phox, rac1 and p67phox. When the cell is stimulated by one of various factors the intracellular components associate with membrane subunits and begin to produce superoxide anion from oxygen. The activity of NAD(P)H oxidase can be controlled by phosphorylation of subunits and/or association of subunits (4). Therefore, the activity of NAD(P)H oxidase is controlled, at least partly, by the expression of these subunits. Recent studies indicate that oxidative stress also plays an important role in cardiovascular changes induced by hypertension. Chronic hypertension, including essential hypertension, is closely related to cardiovascular diseases, and the renin-angiotensin system plays a particularly important role in patients with chronic hypertension. Administrations of angiotensin converting enzyme (ACE) inhibitors or angiotensin II type 1 (AT1) receptor blockers (ARBs) improve hypertension and hypertension-associated cardiovascular diseases. Many reports indicate that angiotensin II, a potent vasopressor, increases oxidative stress in the cardiovascular system through AT1 receptor stimulation. Administration of angiotensin II has been shown to increase superoxide production, NAD(P)H oxidase activity, and pressor response (5, 6). On the other hand, the increase in superoxide production, NAD(P)H oxidase activity and NAD(P)H oxidase subunit expression in experimental vascular injury were inhibited by ARBs without affecting blood pressure (7). These results suggest that angiotensin II modulates oxidative stress mainly by an increase in NAD(P)H oxidase activity through AT1 receptor stimulation. However, the role of angiotensin II in oxidative stress in chronic hypertension has not yet been totally clarified. As an animal model, stroke-prone spontaneously hypertensive rats (SHRSP) are widely used for studies on hypertension. It has been reported that SHRSP developed cardiac hypertrophy (8), brain abnormalities (9) and renal damage (10, 11). In SHRSP, however, the changes in NAD(P)H oxidase subunits were not the same as those observed after continuous infusion of angiotensin II (12, 13). In an article appearing in this issue of Hypertension Research, Akasaki et al. (14) examined the involvement of NAD(P)H oxidase in vascular changes observed in chronic hypertension. The expression of the gp91phox homologues