Vascular Functions of NADPH Oxidases

Abstract

NADPH oxidases belong to a group of enzymes that generate reactive oxygen species (ROS) by electron transfer from NADPH to molecular oxygen. The product of this reaction is the superoxide anion (O 2 Ϫ ), which undergoes secondary reactions. O 2 Ϫ inactivates NO to yield peroxynitrite and spontaneously or under catalysis of superoxide dismutases reacts to hydrogen peroxide. NADPH oxidases, therefore, limit vascular NO availability and facilitate reactions involving ROS. 1 It is now well understood that endothelial dysfunction is largely a consequence of NADPH oxidase activation, as well as of complex secondary reactions that involve different types of ROS. Peroxynitrite oxidizes the NO synthase cofactor tetrahydrobiopterin and stimulates kinases, which both lead to uncoupling of the endothelial NO synthase. NO and O 2 Ϫ may also affect gene expression, and, in particular, NADPH oxidase-derived hydrogen peroxide has been shown to be important in this respect. In addition to the stress-mediated ROS-stimulated gene expression, hydrogen peroxide transiently or irreversibly oxidizes biological materials and, therefore, has complex effects on signaling that are still incompletely elucidated. 1 NADPH Oxidases From Past to PresentAlthough the initial work on NADPH oxidases focused on its role for gene expression and endothelial dysfunction at large, the research of recent years aimed at the identification of specific NADPH oxidase-dependent signaling pathways, the understanding of the role of the enzymes in individual disease entities, the identification of NADPH oxidase inhibitors, and finally the demonstration of a relevance of NADPH oxidases in human cardiovascular diseases. Indeed, it is now known that patients with chronic granulomatous disease, which results from loss-of-function mutations of the NADPH oxidase, have an increased vascular NO availability and reduced vascular levels of footprint markers of ROS formation. 2 This important observation provided a direct link between NADPH oxidase and endothelial function in humans. Chronic granulomatous disease, however, is too rare and too severe to study whether the advantage in endothelial function also translates into a reduced cardiovascular disease rate. Studies on polymorphisms of NADPH oxidase genes, however, failed to draw a clear picture. 3 Thus, most data in support of a relevance of NADPH oxidases for human cardiovascular disease are based on indirect treatment studies. Several highly effective cardiovascular drugs, such as statins, peroxisome proliferator-activated receptor-␥ agonists, angiotensinconverting enzyme inhibitors, and angiotensin II type 1 (AT 1 ) receptor antagonists prevent the activation or induction of NADPH oxidases and reduce the oxidative burden in patients. 4,5 The possible conclusion that NADPH oxidases are excellent cardiovascular drug targets might, however, still be premature, in particular, in light of the failures of large prospective trials testing antioxidants. 6 These studies demonstrated that, although effective in the acute se...

Endothelial Nitric Oxide Synthase-Independent Release of Nitric Oxide in the Aorta of the Spontaneously Hypertensive Rat

“…Indeed, the prevention of the production of ROS obviously plays a key role in the appearance of the endothelium-dependent inhibition of the response to phenylephrine in the SHR aorta. This conclusion is based on the observation that the unmasking effect of indomethacin [which limits the production of ROS in this preparation by inhibition of cyclooxygenase (Tang et al, 2007)] is mimicked by apocynin, which acts mainly as a nonselective antioxidant at the concentration used in the present study (Brandes, 2010).…”

“…However, DPI also can inhibit NADPH oxidases (Griendling et al, 1994), xanthine oxidoreductase (O'Donnell et al, 1993), nitric oxide synthases (Stuehr et al, 1991), and mitochondrial respiration [Complex I (Majander et al, 1994)], all of which could impact on the responses measured in the present study. Different inhibitors of those other enzymes were used to determine whether they would affect the NOS-independent NO release: 1) NADPH oxidase: apocycin, used at a concentration that should inhibit NADPH oxidase besides exerting nonspecific antioxidant properties (Brandes, 2010), decreased rather than increased the contractions evoked by phenylephrine; 2) xanthine oxidoreductase: allopurinol, an inhibitor of xanthine oxidoreductase (Puig et al, 1989) did not reverse the inhibitory effect of the endothelium; 3) nitric oxide synthases: the L-NAME and 1400W experiments already demonstrated that the phenomenon is NOS independent; and 4) mitochondrial respiration (Complex I): Complex III (not Complex I) can transfer nitrite to NO (Kozlov et al, 1999;Nohl et al, 2000), but only in an anoxic environment (Kozlov et al, 1999;Nohl et al, 2000;van Faassen et al, 2009). In the present study, the organ chambers were bubbled with 95% O 2 , which can hardly be considered as an anaerobic condition.…”

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

“…NADPH oxidase, which is activated by AT 1 receptor stimulation, is a major source of ROS (11,17,113,135). The specific brain nuclei that regulate SNA, such as the anteroventral third ventricle, paraventricular nucleus of the hypothalamus, NTS, and the RVLM, are rich in AT 1 receptors (2,10,26,28,83).…”

“…Thus, it is possible that AT 1 receptor blockers reduce oxidative stress in the brain, as well as in the peripheral vasculature. It is also possible that AT 1 receptor blockers inhibit ROS production by blocking AT1 receptormediated intracellular signaling (11,48,50) and that this antioxidant action accounts for the absence of reflex-induced sympathoexcitation after treatment with AT 1 receptor blockers. We evaluated the effects of AT 1 receptor blockers, olmesartan and telmisartan, on brain oxidative stress in SHRSP (4,48).…”

Interaction between Maternal and Offspring Diet to Impair Vascular Function and Oxidative Balance in High Fat Fed Male Mice

“…While low levels of reactive oxygen species (ROS) play a physiological role in cell signalling and vascular function [7], enhanced production or diminished scavenging of these radicals may lead to a reduction in nitric oxide (NO) bioavailability and/or endothelial nitric oxide synthase (eNOS) uncoupling and increased formation of superoxide that are associated with impaired vascular function [8]–[10]. The protective role of endogenous antioxidant mechanisms in cardiovascular disease and their disturbance in obesity related disorders is less clearly defined [7].…”