A gp91phox Containing NADPH Oxidase Selectively Expressed in Endothelial Cells Is a Major Source of Oxygen Radical Generation in the Arterial Wall
Abstract
Abstract —Reactive oxygen species (ROS) play an important role in regulating vascular tone and intracellular signaling; the enzymes producing ROS in the vascular wall are, however, poorly characterized. We investigated whether a functionally active NADPH oxidase similar to the leukocyte enzyme, ie, containing the subunits p22phox and gp91phox, is expressed in endothelial cells (ECs) and smooth muscle cells (SMCs). Phorbol 12-myristate 13-acetate (PMA), a stimulus for leukocyte NADPH oxidase, increased ROS generation in cultured ECs and endothelium-intact rat aortic segments, but not in SMCs or endothelium-denuded arteries. NADPH enhanced chemiluminescence in all preparations. p22phox mRNA and protein was detected in ECs and SMCs, whereas the expression of gp91phox was confined to ECs. Endothelial gp91phox was identical to the leukocyte form as determined by sequence analysis. In contrast, mitogenic oxidase-1 (mox1) was expressed in SMCs, but not in ECs. To determine the functional relevance of gp91phox expression, experiments were performed in aortic segments from wild-type, gp91phox − /− , and endothelial NO synthase (eNOS) − /− mice. PMA-induced ROS generation was comparable in aortae from wild-type and eNOS − /− mice, but was attenuated in segments from gp91phox − /− mice. Endothelium-dependent relaxation was greater in aortae from gp91phox − /− than from wild-type mice. The ROS scavenger tiron increased endothelium-dependent relaxation in segments from wild-type, but not from gp91phox − /− mice. These data demonstrate that ECs, in contrast to SMCs, express a gp91phox-containing leukocyte-type NADPH oxidase. This enzyme is a major source for arterial ROS generation and affects the bioavailability of endothelium-derived NO. ( Circ Res. 2000;87:26-32.)
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NOX2 expression has been reported in other cell types including endothelial cells and adventitial fibroblasts.
“NOX2 expression has been also reported in other cell types including endothelial cells and adventitial fibroblasts (376, 382, 657, 714, 715, 736, 876) (FIGURE 9, Table 5).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [376]
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Expression and Localization of NOX2 and NOX4 in Primary Human Endothelial Cells
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Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance
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The NADPH Oxidase Subunit NOX4 Is a New Target Gene of the Hypoxia-inducible Factor-1
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“Vascular smoothmuscle cells express NOX1-, NOX4- and NOX5-containing enzymes, whereas endothelial cells express in addition the NOX2 protein (Gorlach et al., 2000; Cheng et al., 2001; Bedard and Krause, 2007; BelAiba et al., 2007).”
BackgroundRole of oxidative stress and nitric oxide in atherothrombosis
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“resistance arteries contain Nox-2 (32-36).”
Nitric oxide, oxidative stress, and progression of chronic renal failure
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“formation of the highly oxidizing agent peroxynitrite (ONOO) and limits the availability of NO in the vascular system [11].”
BackgroundInfluentialSelf-citationRole of hydrogen peroxide and oxidative stress in healing responses
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Brar, S. S., Corbin, Z. A., Kennedy, T. P., Hemendinger, R. A., Thornton, L., Bommarius, B., Arnold, R. S., Whorton, A. R., Sturrock, A., Huecksteadt, T. P., et al. (2003) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00525.2002 · Cited by 259 · see citing works
“Thus, as previously reported for vascular tissues (24, 36, 43, 57), airway smooth muscle (11), malignant melanomas (12), and fibroblasts from patients with systemic sclerosis (53), a growth-regulatory NAD(P)H oxidase also appears to have an important role in prostate cancer biology.”
BackgroundTENFREYHAUS, H., HUNTGEBURTH, M., WINGLER, K., SCHNITKER, J., BAUMER, A., VANTLER, M., BEKHITE, M., WARTENBERG, M., SAUER, H., & ROSENKRANZ, S. (2006) · Cardiovascular Research · doi:10.1016/j.cardiores.2006.01.022 · Cited by 259 · see citing works
“In vascular smooth muscle cells (VSMC), expression of Nox1, Nox4, and Nox5 has been detected [9,17,20,35].”
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gp91phox-Containing NADPH Oxidase Mediates Endothelial Dysfunction in Renovascular Hypertension
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Self-citationAngiotensin II Impairs Neurovascular Coupling in Neocortex Through NADPH Oxidase–Derived Radicals
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NOX5 variants are functionally active in endothelial cells
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Induction of NAD(P)H Oxidase by Oxidized Low-Density Lipoprotein in Human Endothelial Cells
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Oxidative Stress Signaling to Chromatin in Health and Disease
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Ghouleh, I. A., Khoo, N. K. H., Knaus, U. G., Griendling, K. K., Touyz, R. M., Thannickal, V. J., Barchowsky, A., Nauseef, W. M., Kelley, E. E., Bauer, P. M., et al. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.06.011 · Cited by 249 · see citing works
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“Recently, overwhelming evidence indicated that nonmitochondrial NAD(P)H oxidases are primarily responsible for the production of O2 in vascular cells on stimulation (10, 52, 64, 105).”
BackgroundReactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression
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VEGF Signaling Through NADPH Oxidase-Derived ROS
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NOX2 and NOX4 Mediate Proliferative Response in Endothelial Cells
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“Vascular endothelial cells possess a gp91phoxcontaining leukocyte-type NOX responsible for arterial ROS generation.(36)”
BackgroundNAD(P)H Oxidase–Dependent Self-Propagation of Hydrogen Peroxide and Vascular Disease
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“The gp91phox containing NADPH oxidase contributes to ROS formation by glia cells, fibroblasts, vascular endothelial cells, and most of all by leukocytes (53, 169).”
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“Extracellular signals like growth factors and cytokines have been shown to increase NAD(P)H oxidase-mediated ROS formation (Görlach et al., 2000a), with subsequent HIF stabilization under normoxic conditions (Richard et al., 2000; Haddad and Land, 2001).”
BackgroundInfluential17β‐Estradiol inhibition of NADPH oxidase expression in human endothelial cells
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“On the other hand, there is mounting evidence that NADPH oxidase, a major source of ROS, namely O2 (2), in endothelial cells (13, 25), plays a critical role in the development of atherosclerosis (14).”
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PKCζ Regulates TNF-α–Induced Activation of NADPH Oxidase in Endothelial Cells
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“In fact, several studies have provided evidence that when vascular cells are supplemented with exogenous NADPH, superoxide production is increased [7,16,17,21,29,30].”
Backgroundp47phox-Dependent NADPH Oxidase Regulates Flow-Induced Vascular Remodeling
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Molecular Characterization of a Superoxide-Generating NAD(P)H Oxidase in the Ventilatory Muscles
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“The majority of ROS, however, occurring in the vascular wall seems to originate from membrane-bound NAD(P)H oxidase (”
BackgroundThe Role of Hydrogen Peroxide in Endothelial Proliferative Responses
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- Authors
- Görlach, A., Brandes, R. P., Nguyen, K., Amidi, M., Dehghani, F., & Busse, R.
- Affiliations
- From the Institut für Kardiovaskuläre Physiologie (A.G., R.P.B., K.N., M.A., R.B.), and Institut für Anatomie II (F.D.), Klinikum der J.W. Goethe-Universität, Frankfurt/Main, Germany.
- Goethe University Frankfurt (DE)
- Corresponding author
- Brandes, R. P.
- Venue
- Circulation Research
- Published
- 2000-07-07
- Volume
- 87
- Issue
- 1
- Pages
- 26-32
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2169235788
- Cited by
- 598
- References
- 28
- Citations by year
- 2026: 3 · 2024: 4 · 2023: 5 · 2022: 14 · 2021: 12 · 2020: 8 · 2019: 11 · 2018: 10 · 2017: 17 · 2016: 23 · 2015: 13 · 2014: 25 · 2013: 18 · 2012: 28
- FWCI
- 26.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutscher Akademischer Austauschdienst
- Deutsche Forschungsgemeinschaft (SFB 553, TP B1)
- Genentech
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- gp91phox, NADPH oxidase, endothelial cells, reactive oxygen species, oxygen free radicals, arterial wall, smooth muscle cells, p22phox, endothelium-dependent relaxation, nitric oxide bioavailability, endothelial nitric oxide synthase, chemiluminescence, Tiron, aorta
- MeSH terms
- NADPH Oxidase 2, Acetylcholine, Animals, Aorta, Endothelium, Vascular, Free Radicals, Membrane Glycoproteins, Muscle, Smooth, Vascular, Nitric Oxide, Tetradecanoylphorbol Acetate, Reactive Oxygen Species, NADPH Oxidases, Reverse Transcriptase Polymerase Chain Reaction, Mice, Rats
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