Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 May 11;110(10):1364-90.
doi: 10.1161/CIRCRESAHA.111.243972.

Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system

Bernard Lassègue  1 , Alejandra San Martín, Kathy K Griendling
Affiliations
Review

Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system

Bernard Lassègue et al. Circ Res. .

Abstract

The NADPH oxidase (Nox) enzymes are critical mediators of cardiovascular physiology and pathophysiology. These proteins are expressed in virtually all cardiovascular cells, and regulate such diverse functions as differentiation, proliferation, apoptosis, senescence, inflammatory responses and oxygen sensing. They target a number of important signaling molecules, including kinases, phosphatases, transcription factors, ion channels, and proteins that regulate the cytoskeleton. Nox enzymes have been implicated in many different cardiovascular pathologies: atherosclerosis, hypertension, cardiac hypertrophy and remodeling, angiogenesis and collateral formation, stroke, and heart failure. In this review, we discuss in detail the biochemistry of Nox enzymes expressed in the cardiovascular system (Nox1, 2, 4, and 5), their roles in cardiovascular cell biology, and their contributions to disease development.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Structure and activation of Nox enzymes
Catalytic Nox subunits, represented in blue, include an N-terminal domain composed of six transmembrane helices, numbered I-VI. Four histidine residues in helices III and V coordinate two heme iron atoms. A cytosolic C-terminal dehydrogenase domain includes an FAD cofactor and an NADPH substrate binding site. Upon activation, electrons are transferred from NADPH to FAD and across the membrane, via heme irons, to molecular oxygen, thus producing superoxide anion, which can be dismutated into hydrogen peroxide. Upper panel. Both Nox1 and Nox2 (blue) form a complex with p22phox (green), with its two transmembrane domains and C-terminal proline-rich region (PRR). A cytosolic complex (orange), is composed of an organizer (Noxo1 or p47phox), an activator (Noxa1 or p67phox) and p40phox (only with p67phox). The organizer, stimulated by phosphorylation (red dots) in the case of p47phox, binds the proline-rich region of p22phox and membrane lipids. Likewise, p40phox binds lipids in endosomal membranes. Rac, activated by GTP (brown dot), binds membrane, Nox and Noxa. The latter subunit triggers FAD reduction. Middle panel. Nox4 (blue) also forms a complex with p22phox (green). Its activity, constitutive in the absence of cytosolic subunits, can be increased by binding of Poldip2 to the cytosolic C-terminal of p22phox. Lower panel. While Nox5S is composed of a catalytic subunit similar to the other oxidases (blue), Nox5L includes an additional N-terminal segment (red) with four EF-hands. Binding of cytosolic calcium to the EF hands triggers Nox5L activation.
Figure 2
Figure 2. Physiological and pathophysiological responses mediated by Nox homologues in cardiovascular cells
This summary of the roles of Nox enzymes in different cell types of the cardiovascular system illustrates the paradox of their mediating both specialized and redundant functions. VSMC, vascular smooth muscle cells; EC, endothelial cells; FB, fibroblasts; CM, cardiomyocytes, MΦ, macrophages; and EPC, endothelial progenitor cells.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Bedard K, Krause KH. The NOX family of ros-generating NADPH oxidases: Physiology and pathophysiology. Physiological reviews. 2007;87:245–313. - PubMed
    1. Bayraktutan U, Blayney L, Shah AM. Molecular characterization and localization of the NAD(P)H oxidase components gp91-phox and p22-phox in endothelial cells. Arteriosclerosis, thrombosis, and vascular biology. 2000;20:1903–1911. - PubMed
    1. Hohler B, Holzapfel B, Kummer W. NADPH oxidase subunits and superoxide production in porcine pulmonary artery endothelial cells. Histochemistry and cell biology. 2000;114:29–37. - PubMed
    1. Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: Specific features, expression, and regulation. American journal of physiology. Regulatory, integrative and comparative physiology. 2003;285:R277–297. - PubMed
    1. Sumimoto H. Structure, regulation and evolution of nox-family NADPH oxidases that produce reactive oxygen species. The FEBS journal. 2008;275:3249–3277. - PubMed

Publication types

MeSH terms