The expression of the NADPH oxidase subunit p22phox is regulated by a redox-sensitive pathway in endothelial cells

Pogrebniak, Alexej; BelAiba, Rachida S.; Bonello, Steve; Wotzlaw, Christoph; Acker, H.; Hess, John; Görlach, Agnes

doi:10.1016/j.freeradbiomed.2004.09.036

Cited by 126 publications

(90 citation statements)

References 43 publications

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“…In line with this argumentation is the detection primarily of NOX2 in pulmonary vascular endothelial cells in our study, as well as 2 recent reports demonstrating a ROS-dependent upregulation of NOX4 in cardiac cells. 41,42 The fact that NOX4 is upregulated in the vessel media in both hypoxia-induced pulmonary hypertension and in human IPAH may be explained by distinct or common regulators of NOX4. With regard to the latter it has been shown that TGF-␤ can upregulate NOX4 in human PASMCs, 20 that hypoxia can increase TGF-␤ in PASMCs, 43 and that interference with TGF-␤ blocks hypoxia-induced vascular remodeling.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Dependent Regulation of Nonphagocytic NADPH Oxidase Subunit NOX4 in the Pulmonary Vasculature

Mittal

Roth

König

et al. 2007

Circulation Research

314

327

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Abstract-Nonphagocytic NADPH oxidases have recently been suggested to play a major role in the regulation of physiological and pathophysiological processes, in particular, hypertrophy, remodeling, and angiogenesis in the systemic circulation. Moreover, NADPH oxidases have been suggested to serve as oxygen sensors in the lung. Chronic hypoxia induces vascular remodeling with medial hypertrophy leading to the development of pulmonary hypertension. We screened lung tissue for the expression of NADPH oxidase subunits. NOX1, NOXA1, NOXO1, p22phox, p47phox, p40phox, p67phox, NOX2, and NOX4 were present in mouse lung tissue. Comparing mice maintained for 21 days under hypoxic (10% O 2 ) or normoxic (21% O 2 ) conditions, an upregulation exclusively of NOX4 mRNA was observed under hypoxia in homogenized lung tissue, concomitant with increased levels in microdissected pulmonary arterial vessels. In situ hybridization and immunohistological staining for NOX4 in mouse lungs revealed a localization of NOX4 mRNA and protein predominantly in the media of small pulmonary arteries, with increased labeling intensities after chronic exposure to hypoxia. In isolated pulmonary arterial smooth muscle cells (PASMCs), NOX4 was localized primarily to the perinuclear space and its expression levels were increased after exposure to hypoxia. Treatment of PASMCs with siRNA directed against NOX4 decreased NOX4 mRNA levels and reduced PASMC proliferation as well as generation of reactive oxygen species. In lungs from patients with idiopathic pulmonary arterial hypertension (IPAH), expression levels of NOX4, which was localized in the vessel media, were 2.5-fold upregulated. These results support an important role for NOX4 in the vascular remodeling associated with development of pulmonary hypertension. (Circ Res. 2007;101:258-267.)Key Words: hypoxia Ⅲ hypoxic pulmonary vasoconstriction Ⅲ NADPH oxidase Ⅲ pulmonary hypertension Ⅲ vascular smooth muscle cell proliferation T he NADPH oxidases are superoxide-generating enzymes that release superoxide by electron transfer from NADPH to oxygen. The classical leukocyte NADPH oxidase plays an important role in host defense against bacterial and fungal pathogens. 1,2 This phagocytic type of NADPH oxidase consists of 2 membrane-bound subunits, gp91 phox and p22 phox which form the flavocytochrome b 558 complex, together with the cyctosolic subunits p40 phox , p47 phox , and p67 phox . Superoxide production by this complex is induced by assembly of the cytosolic and membrane-bound subunits. Such an assembly can be induced by the phosphorylation of p47 phox . 3 Rac GTPases are also involved in this activation process. Recently, several additional isoforms of the membrane-bound subunit gp91phox have been described. The first described homolog of gp91 phox , called mox1 (later NOX1), is primarily expressed in the colon and is suggested to be involved in mitogenic activity. 4 Additional homologs, including NOX3, NOX4 (Renox), NOX5, Duox1, and Duox2, were subsequently described. [5][6][7][8] According to ...

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Section: Discussionmentioning

confidence: 99%

Hypoxia-Dependent Regulation of Nonphagocytic NADPH Oxidase Subunit NOX4 in the Pulmonary Vasculature

Mittal

Roth

König

et al. 2007

Circulation Research

314

327

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“…Cell culture, plasmids, 7,19 -21 short hairpin (sh)RNA, transfection, luciferase assays, ROS measurements, 22 Western blot, 23 Rac activity assays, 24 cAMP and cGMP assays, proliferation assays, 22 in vitro angiogenesis assays, ex vivo mouse aortic explant assays, in vivo mouse Matrigel plug assays, and statistics are described in the expanded Materials and Methods section in the online data supplement, available at http://circres.ahajournals.org.…”

Section: Methodsmentioning

confidence: 99%

“…14,22 In fact, exposure of human umbilical vein endothelial cells (HUVECs) to thrombin (3 U/mL) rapidly increased intracellular ROS levels measured by dichlorofluorescein (DCF) ( Figure 1A) and dihydroethidium (DHE) fluorescence ( Figure 1B) and extracellular ROS levels determined by MCLA chemiluminescence (Figure 1C). We thus determined the involvement of PDE2 in ROS generation by thrombin.…”

Section: Pde2 Mediates Ros Formationmentioning

confidence: 98%

Phosphodiesterase 2 Mediates Redox-Sensitive Endothelial Cell Proliferation and Angiogenesis by Thrombin via Rac1 and NADPH Oxidase 2

Diebold

Djordjevic

Petry

et al. 2009

Circulation Research

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Abstract-Cyclic nucleotide phosphodiesterases (PDEs) control the levels of the second messengers cAMP and cGMP in many cell types including endothelial cells. Although PDE2 has the unique property to be activated by cGMP but to hydrolyze cAMP, its role in endothelial function is only poorly understood. Reactive oxygen species (ROS) have been recognized as signaling molecules controlling many endothelial functions. We thus investigated whether PDE2 would link to ROS generation and proliferative responses in human umbilical vein endothelial cells in response to thrombin. Thrombin stimulated the GTPase Rac1, known to activate NADPH oxidases, and enhanced ROS formation, whereas PDE2 inhibition or depletion by short hairpin (sh)RNA prevented these responses. Similar observations were made with 8-Br-cGMP or atrial natriuretic peptide. In agreement, thrombin elevated cGMP but decreased cAMP levels, whereas db-cAMP or forskolin diminished Rac1 activity and ROS production. Subsequently, PDE2 overexpression activated Rac1, increased ROS generation, and enhanced proliferation and in vitro capillary formation. These responses were not observed in the presence of inactive Rac1 or shRNA against the NADPH oxidase subunit NOX2. Inhibition or depletion of PDE2 also prevented thrombin-induced proliferation and capillary formation. Importantly, downregulation of PDE2 by lentiviral shRNA or PDE2 inhibition prevented vessel sprouting from mouse aortic explants and in vivo angiogenesis in a mouse model, respectively. In summary, PDE2 promotes activation of NADPH oxidase-dependent ROS production and subsequent endothelial proliferation and angiogenesis. Targeting PDE2 may provide a new therapeutic approach in diseases associated with endothelial dysfunction, oxidative stress, vascular proliferation, and angiogenesis.

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“…34 Additionally, NADPH oxidase subunits are upregulated in a feed forward manner, because exogenous H 2 O 2 increased p22 phox expression in both cultured vascular smooth muscle cells 35 and endothelial cells 36 leading to increased NADPH oxidase activity. For these reasons, elevated O 2 ⅐Ϫ in the renal medulla of SS rats on 0.4% salt may "prime" the kidney, making it susceptible to salt-induced oxidative stress and hypertension.…”

Section: Taylor Et Al Renal Medullary Nadph Oxidase and Hypertensionmentioning

confidence: 99%

NADPH Oxidase in the Renal Medulla Causes Oxidative Stress and Contributes to Salt-Sensitive Hypertension in Dahl S Rats

et al. 2006

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Abstract-Dahl salt-sensitive (SS) rats exhibit increased renal medullary oxidative stress and blood pressure salt-sensitivity compared with consomic, salt-resistant SS-13 BN rats, despite highly similar genetic backgrounds. The present study examined potential sources of renal medullary superoxide in prehypertensive SS rats fed a 0.4% NaCl diet by assessing activity and protein levels of superoxide producing and scavenging enzymes. Superoxide production was nearly doubled in SS rats compared with SS-13 BN rats as determined by urinary 8-isoprostane excretion and renal medullary oxy-ethidium microdialysate levels. Medullary superoxide production in tissue homogenates was greater in SS rats, and the NADPH oxidase inhibitor diphenylene iodonium preferentially reduced SS levels to those found in SS-13 BN rats. Dinitrophenol, a mitochondrial uncoupler, eliminated the remaining superoxide production in both strains, whereas inhibition of xanthine oxidase, NO synthase, and cycloxygenase had no effect. L-arginine, NO synthase, superoxide dismutase, catalase, and glutathione peroxidase activities between SS and SS-13 BN rats did not differ. Chronic blood pressure responses to a 4% NaCl diet were then determined in the presence or absence of the NADPH oxidase inhibitor apocynin (3.5 g/kg per minute), chronically delivered directly into the renal medulla. Apocynin infusion reduced renal medullary interstitial superoxide from 1059Ϯ130 to 422Ϯ80 (oxyethidium fluorescence units) and mean arterial pressure from 175Ϯ4 to 157Ϯ6 mm Hg in SS rats, whereas no effects on either were observed in the SS-13 BN . We conclude that excess renal medullary superoxide production in SS rats contributes to salt-induced hypertension, and NADPH oxidase is the major source of the excess superoxide.

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The expression of the NADPH oxidase subunit p22phox is regulated by a redox-sensitive pathway in endothelial cells

Cited by 126 publications

References 43 publications

Hypoxia-Dependent Regulation of Nonphagocytic NADPH Oxidase Subunit NOX4 in the Pulmonary Vasculature

Hypoxia-Dependent Regulation of Nonphagocytic NADPH Oxidase Subunit NOX4 in the Pulmonary Vasculature

Phosphodiesterase 2 Mediates Redox-Sensitive Endothelial Cell Proliferation and Angiogenesis by Thrombin via Rac1 and NADPH Oxidase 2

NADPH Oxidase in the Renal Medulla Causes Oxidative Stress and Contributes to Salt-Sensitive Hypertension in Dahl S Rats

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