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(Circulation Research. 2000;86:365.)
© 2000 American Heart Association, Inc.

Editorials

How Could a Genetic Variant of the p22^phox Component of NAD(P)H Oxidases Contribute to the Progression of Coronary Atherosclerosis?

Michael S. Wolin

From the Department of Physiology, New York Medical College, Valhalla, NY.

Correspondence to Michael S. Wolin, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail mike_wolin{at}nymc.edu

Key Words: atherosclerosis • coronary artery disease • NAD(P)H oxidase • oxidant stress • redox signaling

	Introduction

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Reactive O₂ species (ROS) are thought to contribute to the progression of atherosclerotic coronary artery disease (CAD).^{1 2} In this issue of Circulation Research, Cahilly and colleagues³ provide data supporting an association between a histidine⁷² to tyrosine mutation at the potential site for heme binding of the p22^phox subunit of NAD(P)H oxidases and increased severity and progression of CAD in patients from the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Although it was previously shown that the p22^phox subunit of NAD(P)H oxidases is increased in atherosclerotic human coronary arteries,⁴ its precise role, if any, in disease pathogenesis and the impact of this mutation on the function of NAD(P)H oxidases remain to be elucidated. Given that the p22^phox subunit is a component of both the phagocytic cell oxidase and NAD(P)H oxidases in other cell types in the vessel wall, the mutation could affect the production of ROS and multiple signaling systems that influence the progression of CAD.

The best understood oxidase containing p22^phox is the NADPH oxidase of phagocytic cells (eg, neutrophils and macrophages), which are known to contribute to the development and progression of atherosclerotic vascular disease. Activation of these phagocytic cells causes the cytosolic p47^phox, p67^phox, and p40^phox subunits and the G-protein rac-2 to bind with the membrane-bound flavohemoprotein gp91^phox and p22^phox subunits, producing the superoxide anion (O₂^·-)–generating form of the NADPH oxidase.⁵ The high capacity for O₂^·- production, together with the ability of phagocytes to generate ROS and nitric oxide–derived reactive species, including hypochlorous acid, chloramines, peroxynitrite, and nitrogen dioxide, provides a mechanism to destroy phagocytized materials. These same factors also promote oxidant stress in the phagocytes and adjacent cells in the vessel wall. Although the consequences of phagocyte cell–derived oxidant stress on adjacent cells are not well understood, it is reasonable to hypothesize a contribution to the progression of atherosclerosis through processes involving cell signaling and injury.

Cell types normally present in the vessel wall such as endothelium, vascular smooth muscle (VSM), and fibroblasts also possess p22^phox-containing NAD(P)H oxidases, which could contribute to the progression of CAD.⁶ In contrast to phagocytes, the NAD(P)H oxidases present in these cell types have significant activity in the absence of cellular activation. For example, VSM contains an oxidase whose activity appears regulated by the redox status of cytosolic NAD(H). The O₂ requirements permit this oxidase to function as a physiological PO₂ sensor.⁷ Growth factors for VSM promote vascular proliferation by stimulating NAD(P)H oxidase activity and by increasing the expression of both the p22^phox subunit and a p65^mox subunit, which resembles the gp91^phox subunit of the phagocytic oxidase.^{6 8} Interestingly, the highest levels of p21^phox in human atherosclerotic coronary VSM occur in cells with an undifferentiated phenotype.⁴ In view of the fact that many genes are regulated by PO₂⁹ and ROS^{2 10} signaling mechanisms, factors such as the enhancement of PO₂ gradients as the vessel wall thickens and oxidant stress in CAD could influence the progression of atherosclerosis. In addition, the apparently crucial role of NAD(P)H oxidase–derived ROS in cell growth and responses to stress^{6 11} could be a major contributor to changes that occur in the vessel wall in CAD.

There is currently a lack of essential information regarding the functional consequences of the histidine⁷² to tyrosine mutation. First, although it has been suggested that the histidine⁷² has a role in the binding of heme, the actual function of this residue is not known. Because the mutation is not associated with chronic granulomatous disease, which is seen in patients with defects in other components of the phagocytic NADPH oxidase,^{12 13 14} it is likely that the mutation has relatively subtle effects on the function of the oxidase that remain to be elucidated. Potential consequences of this mutation include an increase or decrease in O₂^·- production by the activated oxidase or disruption of O₂ sensing and processes regulated through alteration of heme binding. Alterations at the heme site of the oxidase could also alter its PO₂ dependence and change the way it would function in O₂ sensing regulated processes. Although there is a very high level of homology between the p22^phox subunits of the phagocytic cell NADPH oxidase and the NAD(P)H oxidase present in VSM, it is currently not known if the mutation is present in the vascular form of the oxidase. Thus, it is not yet possible to predict whether the histidine⁷² to tyrosine mutation directly affects the functions of p22^phox-containing NAD(P)H oxidases in the atherosclerotic vessel wall.

The balance between the production and metabolism of ROS and nitric oxide–derived species in the key intracellular compartments of each cell that populates the atherosclerotic vessel wall influences signaling mechanisms that could contribute to the progression of CAD. For example, this delicate balance influences the expression of adhesion proteins and inflammatory cell activation, redox processes that regulate the production of oxidants by other oxidases, and the function of antioxidant systems, and decisions made by cells related to contractile function, proliferation, responses to stress, apoptosis, and necrosis. Thus, it is highly likely that mutations causing even minor changes in the function of p22^phox-containing NAD(P)H oxidases could influence the progression of CAD. Individual ethnic groups could have other genetic variances or dietary and lifestyle customs, which modify the function of oxidant signaling and antioxidant defense systems that influence the progression of CAD in a manner similar to the mechanisms proposed for fluvastatin.³ Thus, there may be logical explanations for observations made in a Japanese patient group¹⁵ that associate the histidine⁷² to tyrosine mutation with reduced risk of CAD. In addition, HMG-CoA reductase inhibitors may suppress vascular O₂^·- production by preventing mevonate-dependent isoprenylation of the G-protein Rac and assembly of the active form of NAD(P)H oxidases.¹⁶

	Footnotes

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

	References

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