Expression and Distribution of NADPH Oxidase Isoforms in Human Myometrium—Role in Angiotensin II-induced Hypertrophy1

Cui, Xiao; Chang, Baojun; Myatt, Leslie

doi:10.1095/biolreprod.109.080275

Cited by 9 publications

(8 citation statements)

References 70 publications

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“…NOX2 is the most widely distributed isoform and has been shown to play a role in neointimal formation and restenosis [50] , [84] , [88] , however siRNA knockdown of NOX2 did not prevent bFGF upregulation of KCNN4 mRNA expression in our studies. Consistent with previous reports that NOX4 is downregulated during vascular growth and is thought to be primarily responsible for basal cellular O 2 .− production [9] , [26] , [44] , [89] , our findings demonstrate that knockdown of NOX4 does not prevent bFGF upregulation of KCNN4 mRNA expression in CSMCs. These results support previous findings that while increasing ROS production through an NADPH oxidase dependent pathway, bFGF does not upregulate the NOX2 or NOX4 isoforms in human or mouse endothelial cells [90] .…”

Section: Discussionsupporting

confidence: 92%

Upregulation of Intermediate-Conductance Ca2+-Activated K+ Channels (KCNN4) in Porcine Coronary Smooth Muscle Requires NADPH Oxidase 5 (NOX5)

2014

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AimsNADPH oxidase (NOX) is the primary source of reactive oxygen species (ROS) in vascular smooth muscle cells (SMC) and is proposed to play a key role in redox signaling involved in the pathogenesis of cardiovascular disease. Growth factors and cytokines stimulate coronary SMC (CSMC) phenotypic modulation, proliferation, and migration during atherosclerotic plaque development and restenosis. We previously demonstrated that increased expression and activity of intermediate-conductance Ca2+-activated K+ channels (KCNN4) is necessary for CSMC phenotypic modulation and progression of stenotic lesions. Therefore, the purpose of this study was to determine whether NOX is required for KCNN4 upregulation induced by mitogenic growth factors.Methods and ResultsDihydroethidium micro-fluorography in porcine CSMCs demonstrated that basic fibroblast growth factor (bFGF) increased superoxide production, which was blocked by the NOX inhibitor apocynin (Apo). Apo also blocked bFGF-induced increases in KCNN4 mRNA levels in both right coronary artery sections and CSMCs. Similarly, immunohistochemistry and whole cell voltage clamp showed bFGF-induced increases in CSMC KCNN4 protein expression and channel activity were abolished by Apo. Treatment with Apo also inhibited bFGF-induced increases in activator protein-1 promoter activity, as measured by luciferase activity assay. qRT-PCR demonstrated porcine coronary smooth muscle expression of NOX1, NOX2, NOX4, and NOX5 isoforms. Knockdown of NOX5 alone prevented both bFGF-induced upregulation of KCNN4 mRNA and CSMC migration.ConclusionsOur findings provide novel evidence that NOX5-derived ROS increase functional expression of KCNN4 through activator protein-1, providing another potential link between NOX, CSMC phenotypic modulation, and atherosclerosis.

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Section: Discussionsupporting

confidence: 92%

Upregulation of Intermediate-Conductance Ca2+-Activated K+ Channels (KCNN4) in Porcine Coronary Smooth Muscle Requires NADPH Oxidase 5 (NOX5)

2014

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“…The nonreceptor tyrosine kinase c-Abl comigrates with Nox5 to the plasma membrane in a calcium-mediated process (47). Finally, some studies indicate a cytosol location for Nox5 in myocardium (61), myometrium (34), and esophageal carcinoma cells (75). In the latter case, colocalization and functional interplay between the short Nox5S isoform and Rac1 has been reported.…”

Section: Nox5mentioning

confidence: 99%

Nox NADPH Oxidases and the Endoplasmic Reticulum

Laurindo

Araujo

Abrahão

2014

Antioxidants & Redox Signaling

161

138

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Significance: Understanding isoform-and context-specific subcellular Nox reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase compartmentalization allows relevant functional inferences. This review addresses the interplay between Nox NADPH oxidases and the endoplasmic reticulum (ER), an increasingly evident player in redox pathophysiology given its role in redox protein folding and stress responses. Recent Advances: Catalytic/regulatory transmembrane subunits are synthesized in the ER and their processing includes folding, N-glycosylation, heme insertion, p22phox heterodimerization, as shown for phagocyte Nox2. Dual oxidase (Duox) maturation also involves the regulation by ER-resident Duoxa2. The ER is the activation site for some isoforms, typically Nox4, but potentially other isoforms. Such location influences redox/Nox-mediated calcium signaling regulation via ER targets, such as sarcoendoplasmic reticulum calcium ATPase (SERCA). Growing evidence suggests that Noxes are integral signaling elements of the unfolded protein response during ER stress, with Nox4 playing a dual prosurvival/proapoptotic role in this setting, whereas Nox2 enhances proapoptotic signaling. ER chaperones such as protein disulfide isomerase (PDI) closely interact with Noxes. PDI supports growth factor-dependent Nox1 activation and mRNA expression, as well as migration in smooth muscle cells, and PDI overexpression induces acute spontaneous Nox activation. Critical Issues: Mechanisms of PDI effects include possible support of complex formation and RhoGTPase activation. In phagocytes, PDI supports phagocytosis, Nox activation, and redox-dependent interactions with p47phox. Together, the results implicate PDI as possible Nox organizer. Future Directions: We propose that convergence between Noxes and ER may have evolutive roots given ER-related functional contexts, which paved Nox evolution, namely calcium signaling and pathogen killing. Overall, the interplay between Noxes and the ER may provide relevant insights in Nox-related (patho)physiology. Antioxid. Redox Signal. 20, 2755Signal. 20, -2775

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“…AngII also stimulates the production of aldosterone from the adrenal gland, which can participate in these events via the mineralocorticoid receptor [14]. AngII has been reported to influence the expression of Nox subunits, such as Nox1 [69,[228][229][230][231][232], Nox2 [70,[232][233][234], Nox4 [71,230,232] and Nox5 [72,235], and contribute to ROS-mediated damage in a number of pathologies, including hypertension and cardiovascular disease (reviewed in [134,151,236]). Aldosterone can stimulate Nox, with reports that aldosterone/salt infusion increased the expression of Nox isoforms and ROS production [237][238][239][240].…”

Section: Nox the Raas And Retinopathymentioning

confidence: 99%

“…A growing body of evidence indicates that specific isoforms of Nox promote endothelial cell migration and tubulogenesis in vitro [56][57][58][59][60][61] and angiogenesis in vivo [61][62][63][64][65][66]. Attention has also been given to the role of the RAAS in Nox-mediated cell damage [67][68][69][70][71][72], which may be relevant to pathological angiogenesis in ROP and DR, given the established role of the RAAS in both these conditions (reviewed [14]).…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species, Nox and angiotensin II in angiogenesis: implications for retinopathy

et al. 2013

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Pathological angiogenesis is a key feature of many diseases including retinopathies such as ROP (retinopathy of prematurity) and DR (diabetic retinopathy). There is considerable evidence that increased production of ROS (reactive oxygen species) in the retina participates in retinal angiogenesis, although the mechanisms by which this occurs are not fully understood. ROS is produced by a number of pathways, including the mitochondrial electron transport chain, cytochrome P450, xanthine oxidase and uncoupled nitric oxide synthase. The family of NADPH oxidase (Nox) enzymes are likely to be important given that their primary function is to produce ROS. Seven isoforms of Nox have been identified named Nox1-5, Duox (dual oxidase) 1 and Duox2. Nox1, Nox2 and Nox4 have been most extensively studied and are implicated in the development of conditions such as hypertension, cardiovascular disease and diabetic nephropathy. In recent years, evidence has accumulated to suggest that Nox1, Nox2 and Nox4 participate in pathological angiogenesis; however, there is no clear consensus about which Nox isoform is primarily responsible. In terms of retinopathy, there is growing evidence that Nox contribute to vascular injury. The RAAS (renin-angiotensin-aldosterone system), and particularly AngII (angiotensin II), is a key stimulator of Nox. It is known that a local RAAS exists in the retina and that blockade of AngII and aldosterone attenuate pathological angiogenesis in the retina. Whether the RAAS influences the production of ROS derived from Nox in retinopathy is yet to be fully determined. These topics will be reviewed with a particular emphasis on ROP and DR.

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Expression and Distribution of NADPH Oxidase Isoforms in Human Myometrium—Role in Angiotensin II-induced Hypertrophy1

Cited by 9 publications

References 70 publications

Upregulation of Intermediate-Conductance Ca2+-Activated K+ Channels (KCNN4) in Porcine Coronary Smooth Muscle Requires NADPH Oxidase 5 (NOX5)

Upregulation of Intermediate-Conductance Ca2+-Activated K+ Channels (KCNN4) in Porcine Coronary Smooth Muscle Requires NADPH Oxidase 5 (NOX5)

Nox NADPH Oxidases and the Endoplasmic Reticulum

Reactive oxygen species, Nox and angiotensin II in angiogenesis: implications for retinopathy

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