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Review
. 2009 Apr;11(4):791-810.
doi: 10.1089/ars.2008.2220.

NADPH oxidase-dependent signaling in endothelial cells: role in physiology and pathophysiology

Randall S Frey  1 , Masuko Ushio-Fukai, Asrar B Malik
Affiliations
Review

NADPH oxidase-dependent signaling in endothelial cells: role in physiology and pathophysiology

Randall S Frey et al. Antioxid Redox Signal. 2009 Apr.

Abstract

Reactive oxygen species (ROS) including superoxide (O(2)(.-)) and hydrogen peroxide (H(2)O(2)) are produced endogenously in response to cytokines, growth factors; G-protein coupled receptors, and shear stress in endothelial cells (ECs). ROS function as signaling molecules to mediate various biological responses such as gene expression, cell proliferation, migration, angiogenesis, apoptosis, and senescence in ECs. Signal transduction activated by ROS, "oxidant signaling," has received intense investigation. Excess amount of ROS contribute to various pathophysiologies, including endothelial dysfunction, atherosclerosis, hypertension, diabetes, and acute respiratory distress syndrome (ARDS). The major source of ROS in EC is a NADPH oxidase. The prototype phagaocytic NADPH oxidase is composed of membrane-bound gp91phox and p22hox, as well as cytosolic subunits such as p47(phox), p67(phox) and small GTPase Rac. In ECs, in addition to all the components of phagocytic NADPH oxidases, homologues of gp91(phox) (Nox2) including Nox1, Nox4, and Nox5 are expressed. The aim of this review is to provide an overview of the emerging area of ROS derived from NADPH oxidase and oxidant signaling in ECs linked to physiological and pathophysiological functions. Understanding these mechanisms may provide insight into the NADPH oxidase and oxidant signaling components as potential therapeutic targets.

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Figures

FIG. 1.
FIG. 1.
Role OF NADPH Oxidase in endothelial cells. Growth factors, GPCR agonists, cytokines, shear stress, and ischemia/reperfusion activate NADPH oxidase. Oxygen can be converted to superoxide by NADPH oxidase which subsequently leads to the conversion to OH·− radical by lipid peroxides, to H2O2 via superoxide dismutase (SOD), and to H2O and O2 by glutathione peroxidase (GPx) and catalase. O2·− and NO generated from e-NOS can combine to generate ONOO− promoting NOS uncoupling and further O2·− production. The generation of oxidants leads to endothelial dysfunction and permeability, apoptosis and senescence, vascular cell growth and migration, remodeling, and inflammation. The underlying disease progression increases susceptibility to hypertension, atherosclerosis, diabetes, and acute lung injury/sepsis. Feedback mechanisms may also exist in which an existing disease leads to an increase in ROS production. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).
FIG. 2.
FIG. 2.
Schematic diagram of the structure of endothelial NADPH oxidase. (A) Nox1 binds adapter subunits, NoxO1 and NoxA1, in place of the initially characterized gp91phox (Nox2) adapter proteins p47phox and p67phox, respectively, as well as Rac and p22phox. Nox4 activation does not involve p47phox, p67phox, or Rac, while Nox5 has EF hands that bind Ca+2. ?: It is unclear if these proteins are expressed in ECs. Transmembrane topology of Nox enzymes. (B) The predicted transmembrane α-helices contain conserved histidine residues which comprise binding sites for hemes. The carboxyl-terminal domain folds within the cytoplasm and binds to flavin adenine dinucleotide (FAD) and NADPH. The enzymes catalyze the transfer of electrons from NADPH to molecular oxygen, to form O2·− across the membrane. The amino terminal calcium-binding domain of Nox5 enzyme is on the cytosolic side of the membrane. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).
FIG. 3.
FIG. 3.
Role of ROS derived from NADPH oxidase in REDOX-sensitive signaling pathways. Growth factors, GPCR agonists, cytokines, shear stress, and ischemia/reperfusion can activate PKC, PI3K, Akt, Src, MAP kinases, and PAK which stimulate NADPH oxidase to produce ROS. NADPH oxidase-induced ROS can induce oxidative inactivation of protein tyrosine phosphatases, MKP-1 and PTEN to promote downstream redox signaling events. These events are converged and integrated to induce various redox-sensitive transcriptional factors and gene expression, which are involved in EC oxygen sensing, proliferation, senescence, apoptosis, endothelial dysfunction, and permeability and inflammation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).
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