Superoxide Excess in Hypertension and Aging

Abstract

Abstract-There is evidence in humans that hypertension and aging similarly impair endothelial function, although the mechanism remains unclear. Superoxide anion (O 2 Ϫ ) is a major determinant of nitric oxide (NO) bioavailability and thus endothelial function. We sought to determine the relationship between endothelial function, O 2 Ϫ , and age in normotensive Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Aortic rings were removed from female WKY and SHRSP at 3 to 4 months (young) and 9 to 12 months (old). O 2 Ϫ generation by aortic rings was measured before and after removal of the endothelium or incubation with N G nitro-L-arginine methyl ester, diphenyleneiodonium, or apocynin. Levels of p22phox were studied with immunohistochemistry and used as a marker of NAD (P) Key Words: endothelium Ⅲ nitric oxide Ⅲ hypertension, experimental Ⅲ aging T here is evidence that in animal models and in humans, impaired endothelial function and a decrease in nitric oxide (NO) bioavailability may occur in hypercholesterolemia, 1,2 , diabetes, 3 and hypertension 4 -6 despite normal or increased NO production by the endothelium. 6 A decrease in NO bioavailability may also occur with aging. [7][8][9][10] In a number of animal models of disease, including hypertension 11,12 and hypercholesterolemia, 13 an increase in superoxide (O 2 Ϫ ) occurs concurrent to the decrease in NO bioavailability. O 2 Ϫ rapidly reacts with NO, forming peroxynitrite and decreasing NO bioavailability. 14 Thus, it has been proposed that elevations in O 2 Ϫ levels contribute to the impaired endothelial function associated with atherosclerotic disease. 13,15 Taddei et al 9 proposed that the endothelial dysfunction that occurs in hypertension represents an accelerated form of the dysfunction that occurs with aging. However, the effects of aging on O 2 Ϫ production are less well defined. Huraux and colleagues 16 observed a negative correlation between O 2 Ϫ levels and age in human internal mammary arteries. In contrast, Berry et al 17 found basal O 2 Ϫ production in human internal mammary arteries to be weakly but positively associated with age. Potential vascular sources of O 2 Ϫ are endothelial NO synthase (eNOS), 18 xanthine oxidase, 19 and NAD(P)H oxidase. 20,21 eNOS 18 and NAD(P)H oxidase 22,23 have been proposed to be involved in O 2 Ϫ production in different models of hypertension, whereas xanthine oxidase may be involved in O 2 Ϫ production in hypercholesterolemia. 13 eNOS can be inhibited by arginine analogues such as N G nitro-L-arginine methyl ester (L-NAME). NAD(P)H oxidase is composed of at least 5 subunits, and apocynin can inhibit enzymatic activity by preventing association of the subunits. Diphenyleneiodonium (DPI) is a less specific inhibitor of flavincontaining oxidases, including NAD(P)H oxidase.In this study, the hypothesis that both hypertension and aging result in increased levels of O 2 Ϫ and decreased NO bioavailability in blood vessels from Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertens...

The effect of p22phox −930A/G, A640G and C242T polymorphisms of NADPH oxidase on peripheral and central pressures in healthy, normotensive individuals

“…24 Moreover, advanced age increases expression of p22 phox , with a concomitant increase in superoxide anion production from the endothelium and the adventitia in a rodent model. 25 Taken together, these results raise the possibility that carriers of the G allele may develop a greater risk of cardiovascular mishap on account of exposure to multiple vascular injurious stimuli.…”

Nox2-Derived Reactive Oxygen Species Mediate Neurovascular Dysregulation in the Aging Mouse Brain

“…Some reports have described an increase in NADPH oxidase subunits in systemic blood vessels (Adler et al, 2003;Hamilton et al, 2001;Oudot et al, 2006), whereas others have not (Bachschmid et al, 2004;Csiszar et al, 2002;Newaz et al, 2006). Other studies have used non-specific pharmacological inhibitors, such as DPI or apocyanin, to assess the contribution of NADPH oxidase to ROS production and/or cardiovascular dysfunction (Adler et al, 2003;Csiszar et al, 2002;Hamilton et al, 2001). In this study, using both a peptide inhibitor and Nox2-null mice we have been able to provide, for the first time, converging evidence that a Nox2-containing NADPH oxidase is a key factor in the cerebrovascular dysfunction produced by aging.…”

Superoxide as a Messenger of Endothelial Function

“…Recently, it has been shown that incubation of aortic vessels derived from 1-year-old rats with the NAD(P)H oxidase inhibitors DPI and apocynin resulted in a significant decrease in • O 2 -production (Hamilton et al, 2001). However, those inhibitors are not specific for NAD(P)H oxidase and may also act on other oxidases.…”