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  • Review Article
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Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets

Nature Reviews Drug Discovery volume 10, pages 453–471 (2011)Cite this article

Subjects

Key Points

  • NADPH oxidases are a family of enzymes that generate reactive oxygen species (ROS). The ROS generated by NADPH oxidases have crucial roles in various physiological processes, including innate immunity and modulation of redox-dependent signalling cascades.

  • Excessive ROS production by an overactive NADPH oxidase system in cells of the artery wall may set in motion a vicious cycle of radical and non-radical oxidant generation in various cellular compartments, which disrupts redox circuits. This can lead to the initiation and progression of vascular disease that may ultimately lead to heart attacks and strokes.

  • Blocking excessive ROS production by blocking NADPH oxidases is likely to be a far superior approach for preventing the progression of vascular disease than using antioxidant drugs, which scavenge ROS.

  • This Review first provides an overview of the mechanisms by which ROS can cause vascular disease and the possible reasons why previous attempts to eliminate these species with antioxidants failed. We summarize the evidence that NADPH oxidases are key generators of ROS — in the blood vessel wall and other tissues — during cardiovascular diseases, with a particular focus on the NADPH oxidase 1 (NOX1) and NOX2 oxidase isoforms.

  • We also describe some common and emerging putative NADPH oxidase inhibitors.

  • In addition, we highlight the crucial role of the NADPH oxidase regulatory subunit, p47phox, in the activity of vascular NOX1 and NOX2 oxidases, and suggest how a better understanding of its specific molecular interactions may enable the development of novel isoform-selective drugs to prevent or treat cardiovascular diseases.

Abstract

NADPH oxidases are a family of enzymes that generate reactive oxygen species (ROS). The NOX1 (NADPH oxidase 1) and NOX2 oxidases are the major sources of ROS in the artery wall in conditions such as hypertension, hypercholesterolaemia, diabetes and ageing, and so they are important contributors to the oxidative stress, endothelial dysfunction and vascular inflammation that underlies arterial remodelling and atherogenesis. In this Review, we advance the concept that compared to the use of conventional antioxidants, inhibiting NOX1 and NOX2 oxidases is a superior approach for combating oxidative stress. We briefly describe some common and emerging putative NADPH oxidase inhibitors. In addition, we highlight the crucial role of the NADPH oxidase regulatory subunit, p47phox, in the activity of vascular NOX1 and NOX2 oxidases, and suggest how a better understanding of its specific molecular interactions may enable the development of novel isoform-selective drugs to prevent or treat cardiovascular diseases.

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Figure 1: Subunit composition of the seven mammalian NADPH oxidase isoforms.
Figure 2: Cellular and subcellular expression of NADPH oxidase isoforms in the blood vessel wall.
Figure 3: Schematic diagram showing p47phox as the central organizer of the vascular NOX1 and NOX2 oxidases.
Figure 4: The p47phox tandem-repeat SH3 domain as a potential drug target.

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Acknowledgements

The authors are grateful to R. Brandes, F. Faraci, C. Iadecola and P. Pagano for their expert advice during the preparation of this manuscript, and to J. Rivera for compiling the information presented in Table 1. We also acknowledge the National Health and Medical Research Council of Australia for Fellowship and Project Grant support (IDs 606472, 1006017, 545942, 570861, 606488 and 1010984), the Heart Foundation of Australia for Grant-in-aid support (G 09M 4398 and G 10M 5218), the Cancer Council of Victoria for a Project Grant (606674), and the US National Institutes of Health for grant support (HL38206, HL058863, HL092120 and HL095070).

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Authors and Affiliations

  1. Department of Pharmacology, Vascular Biology & Immunopharmacology Group, Monash University, 3800, Victoria, Australia

    Grant R. Drummond, Stavros Selemidis & Christopher G. Sobey

  2. Division of Cardiology, Emory University, Atlanta, 30322, Georgia, USA

    Kathy K. Griendling

Authors
  1. Grant R. Drummond
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  2. Stavros Selemidis
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  4. Christopher G. Sobey
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Correspondence to Grant R. Drummond.

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Glossary

Innate immunity

The first line of defense against invading microorgansims. This is mediated by a combination of anatomical barriers (such as skin and internal epithelial surfaces), physiological barriers (such as raised body temperature), secretory molecules (such as digestive enzymes, complement and interferons) and certain kinds of leukocytes (such as macrophages, neutrophils, mast cells and so on).

Microbicidal burst

The rapid release of reactive oxygen species such as superoxide and hydrogen peroxide by white blood cells (for example, neutrophils and macrophages) to eliminate invading microorganisms from the body.

Oxidative stress

An imbalance between the production and inactivation of reactive oxygen species within a biological system, which often results in redox-sensitive modification of macromolecules — including proteins, nucleotides and lipids — and leads to cellular toxicity.

Professional phagocytes

Cells that are able to engulf (phagocytose) particles such as invading pathogens, dead host cells and cell debris with high efficiency. Such cells include monocytes, macrophages, neutrophils, dendritic cells and mast cells.

Acute cardiovascular events

Cardiovascular end points — such as stroke and heart attacks — that result from the sudden cessation of blood flow through arteries owing to a stenosis or a thromboembolus.

Arterial remodelling

A term used to describe any persistent change in the cross-sectional area of a blood vessel. Remodelling may be outward, in which the vessel expands to accommodate a stenosis, or inward, as a result of medial hypertrophy in hypertension, intimal thickening owing to atherosclerosis, transplant vasculopathy or restenosis after balloon angioplasty.

Thrombosis

The formation of a blood clot within a blood vessel.

Restenosis

The reoccurrence of a stenosis leading to restricted blood flow, occurring at a site on the artery that received angioplasty treatment to clear an initial stenosis.

Atherosclerotic plaque

An accumulation of inflammatory cells — mainly macrophages — and cell debris containing lipids, cholesterol, calcium and fibrous connective tissue, which leads to the enlargement of the artery wall.

Redox state

The reduction or oxidation state of a molecule, which is governed by the number of electrons gained or transferred in a chemical reaction.

Adhesion molecules

Integral membrane proteins including integrins, selectins and certain immunoglobulins that mediate the binding of one cell to other cells or extracellular matrix proteins.

Metalloproteinases

A family of protease enzymes possessing a metal centre (most often Zn2+) as the key functional group in their catalytic site.

Inflammasomes

Multiprotein signalling platforms that are activated in response to pathogens or host-derived stress signals that trigger the maturation of pro-inflammatory cytokines such as interleukin-1β and interleukin-18.

Cohort studies

An analytical study that follows the same group of people over a long period of time and is often used to assess risk of disease.

Endothelial dysfunction

A shift in the activation state of the endothelium towards reduced production of vasodilator substances, such as nitric oxide, and increased production of pro-inflammatory and prothrombotic mediators.

EF hand motifs

A protein structural domain that is involved in binding Ca2+, and is characterized by a helix–loop–helix topology that has a conformation similar in shape to the spread thumb and forefinger of the hand.

Binding pockets

Regions on a protein that other smaller molecules, termed ligands, can dock onto in a highly specific fashion through the formation of chemical bonds. Such ligands can include endogenous factors such as hormones or neurotransmitters, or exogenous substances such as drugs.

X-ray crystallography

A method of determining the three-dimensional arrangement of atoms within a crystalline substance based on the diffraction pattern generated following bombardment of the crystal with a beam of X-rays.

Phox homology (PX) domain

A conserved protein structural domain that is involved in the targeting of proteins to cellular membranes by binding to phosphoinositides.

Phage display mapping

A method for the study of protein–protein interactions in which proteins of interest are immobilized and exposed to peptide-presenting bacteriophages. Bacteriophages that bind to the protein are used to infect a bacterial host from which the phagemid is collected and the relevant DNA is sequenced and used to predict the primary sequence of the bound peptide.

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Drummond, G., Selemidis, S., Griendling, K. et al. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov 10, 453–471 (2011). https://doi.org/10.1038/nrd3403

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