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(Circulation. 2005;112:2585-2588.)
© 2005 American Heart Association, Inc.

Editorial

Oxidative Stress and the Vascular Wall

NADPH Oxidases Take Center Stage

John F. Keaney, Jr, MD

From the Evans Memorial Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass.

Correspondence to John F. Keaney, Jr, MD, Evans Memorial Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, 02118. E-mail jkeaney{at}bu.edu

Key Words: Editorials • calcium • NADPH oxidase • stress

The contemporary notion that oxidative stress contributes to vascular wall pathology dates back some 25 years, when chemical modification of LDL was found to permit macrophage foam cell formation,¹ and subsequent data indicated that vascular cells promoted LDL lipid oxidation (eg, LDL oxidation) to produce a similarly modified LDL.² It is now clear, however, that oxidative stress in the vascular wall involves much more than the oxidation of LDL lipids. Risk factors for atherosclerosis are associated with an increased arterial wall flux of reactive oxygen species that not only may oxidize biological targets (ie, lipids), but also directly produce phenotypic changes in vascular cells such as inducing smooth muscle cell proliferation, adhesion molecule expression, and premature senescence.³ Many of these cellular responses have been implicated in both the development and the clinical manifestations of atherosclerosis.

Articles pp 2668 and 2677

In the cellular environment, the most common reactive oxygen species produced is superoxide (O₂·^–) because it is the product of a single electron added to oxygen. Cells and tissues contain abundant superoxide dismutase that converts superoxide to hydrogen peroxide (H₂O₂), a species that has garnered considerable interest as an endogenous signaling molecule. A landmark study by Sundaresan and colleagues⁷ demonstrated a requirement for intracellular H₂O₂ generation in the mitogenic effects of platelet-derived growth factor on smooth muscle. Subsequent investigation points to a host of phenotypic responses that involve intracellular reactive oxygen species as signaling molecules (reviewed by Chen et al⁸). As a result of this body of work, one can construct a paradigm (Figure 1) relating cellular responses to the phenotype of the vascular wall. In this model, the presence or absence of vascular disease represents a balance between tissue responses typically categorized as either normal or related to injury. With regard to the former, a normal vasculature is characterized by laminar flow, endothelial elaboration of nitric oxide (NO·), and the resultant vasodilation, inhibition of platelet adhesion, low matrix turnover, and smooth muscle cells historically described as "quiescent." In contrast, vascular disease is characterized by an injury response that involves mediators such as angiotensin to induce production of cellular reactive oxygen species that, in part, mediate vasoconstriction, matrix turnover, and a "proliferative" smooth muscle cell phenotype. According to this paradigm, one may propose that vascular disease represents a dysregulation of the injury response. Because the cellular generation of reactive oxygen species is a critical part of this response,⁹ understanding the mechanism(s) of injury-related reactive oxygen species production has become a subject of considerable interest.

View larger version (42K): [in this window] [in a new window]   Figure 1. Paradigm demonstrating opposing effects of reactive oxygen species-mediated signaling in contrast with that of nitric oxide. NO tends to promote quiescent phenotype associated with laminar flow and normal arteries. In contrast, reactive oxygen species mediated signals typically mediate "injury"-related responses promoted by growth factors associated with occurrence of vascular disease.

Among the cellular sources of reactive oxygen species associated with injury, NADPH oxidase is perhaps the best characterized. This multicomponent enzyme consists of cytosolic accessory proteins (Rac, p47^phox, p67^phox) that, on stimulation, associate with the membrane catalytic subunits (Nox, p22^phox) to facilitate superoxide generation (Figure 2).^10,11 For many years, this enzyme was thought to exist as a single isoform only in phagocytes and its function restricted to antimicrobial action. This notion changed drastically with the discovery of multiple Nox isoforms that now represent an enzyme family containing at least 5 members. The phagocyte enzyme is now known as Nox2,¹² and several members of this Nox family exist in vascular cells (Figure 2), with many appearing to be upregulated in the setting of atherosclerosis⁵ and arterial injury.^9,16 Consistent with these observations, the activity of this enzyme family has been implicated in atherosclerosis, hypertension, and the response to arterial injury.

View larger version (54K): [in this window] [in a new window]   Figure 2. NADPH oxidase (Nox) in vasculature. Top, neutrophil NADPH oxidase paradigm generalized to all Nox isoforms. Cellular stimulation produces assembly of cytosolic and membrane oxidase subunits to generate superoxide (O2·–) often metabolized in cells to hydrogen peroxide. The neutrophil enzyme is now known as Nox2 and subunit requirements for other Nox isoforms are not known with certainty. In neutrophils, cell stimulation involved host invasion, whereas vascular oxidases are thought to be activated by agents associated with vascular injury. Bottom, Nox isoform expression in vascular wall cells.

Although there is considerable enthusiasm for the involvement of NADPH oxidases in the pathogenesis of vascular disease, much of the supportive evidence is circumstantial. Although it is known that the neutrophil oxidase (Nox2) requires p22^phox, p47^phox, and Rac1 for full activity,¹⁷ our knowledge concerning the contribution of these proteins to other Nox isoform activity is not yet clear. As a consequence, little information exists on the individual Nox family members with regard to their contribution to vascular pathology. Two important articles in this issue of Circulation have broken new ground and have begun to bridge this gap in knowledge with regard to the Nox1 isoform of NADPH oxidase. Dikalova and colleagues¹⁸ used a "gain-of-function" strategy to overexpress Nox1 and determine its implications for vascular pathology. In particular, they used elegant genetic techniques to specifically overexpress Nox1 in smooth muscle cells where this isoform has been implicated in the response to angiotensin II.¹¹ They found that overexpression of Nox1 in smooth muscle produced a basal increase in vascular reactive oxygen species production without any overt vascular pathology.¹⁸ In response to angiotensin II infusion, however, animals with smooth muscle cell Nox1 overexpression demonstrated greatly exaggerated hypertension and medial arterial hypertrophy as compared with animals with normal Nox1 levels.¹⁸ These data are consistent with published observations that angiotensin II–induced reactive oxygen species production induces smooth muscle cell hypertrophy¹⁹ and contributes to the angiotensin II–induced hypertensive response.²⁰ The work by Dikalova and colleagues¹⁸ specifically identifies smooth muscle cell Nox1 as a plausible source of angiotensin II–induced reactive oxygen species production and supports the notion that Nox1 contributes to angiotensin II–mediated vascular pathology. Given the broad efficacy of angiotensin-converting enzyme inhibitors to ameliorate vascular disease,²¹ the data by Dikalova and coworkers would support speculation that Nox1 may contribute to atherosclerosis in general.

Given previous data that NADPH oxidase is required for angiotensin II–induced smooth muscle cell hypertrophy,¹⁹ it is notable that overexpression of Nox1 alone only induced mild medial hypertrophy with no hypertension despite a demonstrable increase in the reactive oxygen species signal.¹⁸ The authors explain these findings by noting compensatory upregulation of antioxidant enzymes (eg, catalase, manganese superoxide dismutase), that potentially mitigated the influence of reactive oxygen species. One must also consider, however, an alternative interpretation that reactive oxygen species from Nox1 are not sufficient to recapitulate the entire spectrum of the vascular wall angiotensin II response. This view coincides with in vitro data that angiotensin II induces reactive oxygen species–dependent and –independent responses that are both required for smooth muscle cell hypertrophy.²² Under this scenario, reactive oxygen species–mediated signals would best be viewed as either permissive or exerting a modulatory influences on vascular phenotype rather than being strictly required for specific cellular responses. In this regard, the role of reactive oxygen species could be likened to that of NO, a signaling molecule with a largely modulatory role in the vasculature that often counterbalances phenotypic responses associated with reactive oxygen species (Figure 1).

In a classic complement to the "gain-of-function" strategy employed by Dikalova and coworkers,¹⁸ the study by Matsuno and colleagues²³ employs a "loss-of-function" approach. These investigators created mice deficient in Nox1 by disrupting the Nox1 gene. Because the gene is on the X chromosome, it was possible to study male mice (eg, Nox1^–/Y) to determine the effect of Nox1 on the response to angiotensin II. Compared with wild-type mice, Nox1-null mice exhibited attenuation of both the reactive oxygen species flux and the hypertensive response to angiotensin II after 7 days of treatment.²³ These findings are in total agreement with the notion that Nox1-derived reactive oxygen species contribute to angiotensin II–induced hypertension.¹⁸ The angiotensin II–induced increase in medial hypertrophy was not blunted in Nox1-null mice despite this reduced blood pressure. These data by Matsuno and colleagues suggest that Nox1 is not necessary for angiotensin II–induced medial hypertrophy, a finding that contrasts with the conclusions derived from Nox1 overexpressing mice.¹⁸

How can we reconcile the findings from these 2 studies? One possible explanation relates to the different strategies employed: enzyme overexpression versus deletion. The former approach requires considerable care with regard to interpretation. In any study that uses overexpression of a protein, it is possible that the extent of overexpression does not mimic the situation normally observed in nature, with the potential consequence of introducing nonspecific effects. Focusing on the study of Dikalova and colleagues,¹⁸ it seems that Nox1 overexpression afforded an angiotensin II–induced reactive oxygen species flux far exceeding that observed with angiotensin infusion alone. In this instance, it is possible that an "excess" nonphysiological reactive oxygen species flux produced additional medial hypertrophy. Indeed, it is known that the smooth muscle cell response to reactive oxygen species is highly dose dependent.²⁴ Another possible reason for the discrepancy between studies is that reactive oxygen species could be responsible for the medial hypertrophy, but any source will suffice. This contention is consistent with observations that compared with normal animals, angiotensin II still produced an increased (albeit blunted) reactive oxygen species flux in Nox1-null mice in association with the upregulation of Nox2 and Nox4.²³ This Nox1-independent reactive oxygen species flux could be sufficient to support the medial hypertrophy. Data from Dikalova and colleagues¹⁸ that tempol (an antioxidant compound) attenuated both the reactive oxygen species signal and medial hypertrophy in response to angiotensin II would tend to support this viewpoint.

Despite their differences, these 2 studies add collectively to our understanding of vascular pathology. For example, both studies demonstrated that Nox1-derived reactive oxygen species have an impact on the hypertensive response to angiotensin II,^18,23 perhaps through scavenging of NO, a potent vasodilator known to regulate blood pressure. In addition, both studies have effectively separated hemodynamic responses from effects on medial hypertrophy. In saline-treated animals, Dikalova and colleagues found medial hypertrophy with Nox1 overexpression in the absence of hypertension,¹⁸ whereas Matsuno et al demonstrated reduced angiotensin II–induced hypertension in Nox1-null mice with no effect on hypertrophy.²³ Together, these findings are consistent with a previous report that mice deficient in another NADPH oxidase isoform (Nox2) have no defect in angiotensin II–induced hypertension, but do exhibit significant attenuation of both the reactive oxygen species signal and medial hypertrophy compared with wild-type mice.²⁵ Thus, emerging evidence clearly indicates that angiotensin II may induce medial hypertrophy independent of changes in blood pressure. If these data extend to humans, then it could provide important insights into how abnormalities of vascular architecture may precede the development of hypertension.

The studies presented in this issue of Circulation^18,23 and the work of Wang and colleagues²⁵ differ with regard to the isoform of NADPH oxidase under study. This is not a trivial point because Nox isoforms are known to differ with respect to cell-specific expression (Figure 2) and intracellular sites of localization. With regard to the former, Nox2 expression is restricted to the endothelium and adventitia,²⁵ whereas Nox1 is expressed only in smooth muscle and periadventitial fat¹⁸ and requires angiotensin for significant upregulation. In endothelial cells, Nox2 is predominantly perinuclear and near the endoplasmic reticulum,²⁶ whereas smooth muscle cell Nox1 colocalizes with caveolin at the plasma membrane.²⁷ It seems likely that these differences among NADPH oxidase isoforms reflect distinct functions and molecular targets. This speculation is supported by abundant literature on the NO synthase (NOS) enzymes that produce NO, another freely diffusible signaling molecule. The cellular response to NO production can vary dramatically depending on its site of synthesis. For example, in cardiac myocytes NOS3 is localized to caveolae and regulates L-type Ca²⁺ channels.²⁸ In contrast, NOS1 resides in the sarcoplasmic reticulum, where it regulates ryanodine receptor Ca²⁺ release.²⁸ Given that NO and reactive oxygen species such as H₂O₂ share similar chemical properties (reviewed by Chen et al⁸), it is not surprising that the site(s) of reactive oxygen species production could dictate the resultant phenotypic response(s).

In summary, the 2 genetic models of Nox1 manipulation presented here represent an important milestone in research relating oxidative stress to vascular disease. It is clear that NADPH oxidases play a role in vascular pathology and the control of vascular phenotype. We need more models in which the genes for various NADPH oxidase isoforms are either overexpressed or deleted. Only with the advent of these models can we hope to test the precise contribution of NADPH oxidases in vascular pathology. Because injury and inflammation are known to be important for vascular disease, understanding the role of NADPH oxidases in these processes is of paramount importance, and this knowledge may help us develop new strategies for the treatment of cardiovascular disease.

	Footnotes

 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

	References

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Keaney, J. F. Search for Related Content PubMed PubMed Citation Articles by Keaney, J. F., Jr Related Collections Oxidant stress Pathophysiology Risk Factors