A Ca2+-activated NADPH Oxidase in Testis, Spleen, and Lymph Nodes

Bánfi, Botond; Molnár, Gergely; Maturana, Andrés D.; Steger, Klaus; Hegedűs, Balázs; Demaurex, Nicolas; Krause, Karl Heinz

doi:10.1074/jbc.m103034200

Cited by 540 publications

(556 citation statements)

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“…Despite advances in Nox research, progress in Nox5 biology, especially in the cardiovascular system, in in vivo settings , has been slow because of lack of research tools and experimental models. Nox5 was originally identified in testis, ovaries, spleen, and immature lymphocytes and is heavily expressed in various cancers 17. More recently, Nox5 has been demonstrated in the vascular system.…”

Section: Discussionmentioning

confidence: 99%

“…During evolution, for unknown reasons, the Nox5 gene was lost in rodents, but is present and functionally active in some invertebrates and in higher mammals 17. Arthropods possess Nox5, an ortholog of human Nox5, besides dual oxidase, and some of them also possess Nox4‐art, a gene related to Nox4 31, 49.…”

Section: Discussionmentioning

confidence: 99%

“…Nox5 is the only Nox isoform that has been crystalized 16. Unique to Nox5 is its long N‐terminal extension that contains 4 calcium (Ca 2+ )‐binding EF hands, which undergoes conformational change upon Ca 2+ binding 17, 18. Increased intracellular free Ca 2+ concentration ([Ca 2+ ] i ) is essential for the activity of Nox5,18, 19, 20 as evidenced in cell‐culture studies where ROS are not synthesized in Ca 2+ ‐free buffer or from cells with truncation of the N‐terminal region of Nox5 21.…”

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confidence: 99%

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NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Montezano

Camargo

Persson

et al. 2018

JAHA

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BackgroundNADPH Oxidase 5 (Nox5) is a calcium‐sensitive superoxide‐generating Nox. It is present in lower forms and higher mammals, but not in rodents. Nox5 is expressed in vascular cells, but the functional significance remains elusive. Given that contraction is controlled by calcium and reactive oxygen species, both associated with Nox5, we questioned the role of Nox5 in pro‐contractile signaling and vascular function.Methods and ResultsTransgenic mice expressing human Nox5 in a vascular smooth muscle cell–specific manner (Nox5 mice) and Rhodnius prolixus, an arthropod model that expresses Nox5 endogenoulsy, were studied. Reactive oxygen species generation was increased systemically and in the vasculature and heart in Nox5 mice. In Nox5‐expressing mice, agonist‐induced vasoconstriction was exaggerated and endothelium‐dependent vasorelaxation was impaired. Vascular structural and mechanical properties were not influenced by Nox5. Vascular contractile responses in Nox5 mice were normalized by N‐acetylcysteine and inhibitors of calcium channels, calmodulin, and endoplasmic reticulum ryanodine receptors, but not by GKT137831 (Nox1/4 inhibitor). At the cellular level, vascular changes in Nox5 mice were associated with increased vascular smooth muscle cell [Ca2+]i, increased reactive oxygen species and nitrotyrosine levels, and hyperphosphorylation of pro‐contractile signaling molecules MLC20 (myosin light chain 20) and MYPT1 (myosin phosphatase target subunit 1). Blood pressure was similar in wild‐type and Nox5 mice. Nox5 did not amplify angiotensin II effects. In R. prolixus, gastrointestinal smooth muscle contraction was blunted by Nox5 silencing, but not by VAS2870 (Nox1/2/4 inhibitor).ConclusionsNox5 is a pro‐contractile Nox isoform important in redox‐sensitive contraction. This involves calcium‐calmodulin and endoplasmic reticulum–regulated mechanisms. Our findings define a novel function for vascular Nox5, linking calcium and reactive oxygen species to the pro‐contractile molecular machinery in vascular smooth muscle cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Montezano

Camargo

Persson

et al. 2018

JAHA

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“…In human and rodent VSM cells, Nox1 and Nox4 expression have been documented [65,80,98,140,163], and Nox2 expression has also been reported in some human VSM cells [79,155]. Nox5 may be expressed in human VSM cells but not in rodent [8].…”

Section: Regulation Of Nadph Oxidasementioning

confidence: 99%

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

Ginnan

Guikema

Halligan

et al. 2008

Free Radical Biology and Medicine

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Inflammation plays a critical role in promoting smooth muscle migration and proliferation during vascular diseases such as post-angioplasty restenosis and atherosclerosis. Another common feature of many vascular diseases is the contribution of reactive oxygen (ROS) and nitrogen (RNS) species to vascular injury. Primary sources of ROS and RNS in smooth muscle are several isoforms of NADPH oxidase (Nox) and the cytokine-regulated inducible nitric oxide (NO) synthase (iNOS). One important example of the interaction between NO and ROS is the reaction of NO with superoxide to yield peroxynitrite, which may contribute to the pathogenesis of hypertension. In this review, we discuss the literature that supports an alternate possibility: Nox-derived ROS modulate NO bioavailability by altering the expression of iNOS. We highlight data showing co-expression of iNOS and Nox in vascular smooth muscle and demonstrating the functional consequences of iNOS and Nox during vascular injury. We describe the relevant literature demonstrating that the mitogen activated protein kinases (MAP kinases) are important modulators of pro-inflammatory cytokinedependent expression of iNOS. A central hypothesis discussed is that ROS-dependent regulation of the serine/threonine kinase protein kinase Cδ (PKCδ) is essential to understanding how Nox may regulate signaling pathways leading to iNOS expression. Overall, the integration of non-phagocytic NADPHoxidase with cytokine signaling in general and in vascular smooth muscle in particular is poorly understood and merit further investigation.

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“…This process has been shown to significantly contribute to intracellular acidification in phagocytes [5;6]. To counteract the cytosolic acidification during NADPH oxidation, it has been suggested that NADPH oxidase functions at the same time as a H + channel to support H + release from cells [7], and recombinant expression of several NADPH oxidase isoforms have been shown to result in a plasma membrane H + conductance, including Nox2 [8], Nox5 [9], and a truncated form of Nox1 [1]. However, this conclusion was challenged early on owing to i) the expression of the Nox constructs in cell systems that already expressed native H + currents, ii) a lack of H + selectivity of the resulting currents, and iii) the much shorter time constants of current activation recorded after Nox expression in these studies when compared to time constants of native H + currents [10;11].…”

Section: Introductionmentioning

confidence: 99%

Expression of Nox1 in 3T3 cells increases cellular acid production but not proton conductance

Gaggioli¹,

Schwarzer²,

Fischer³

2007

Archives of Biochemistry and Biophysics

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The role of the NADPH oxidase homolog 1 (Nox1) in plasma membrane H + conductance and cellular H + production was investigated in 3T3 cells stably expressing Nox1 (Nox1 3T3) compared to vectorexpressing control cells (mock 3T3). In whole cell patch clamp experiments both Nox1 and mock 3T3 expressed a similar H + conductance (Nox1 3T3, 13.2 ± 8.6 pS/pF; mock 3T3, 16.6 ± 13.4 pS/ pF) with a number of similar characteristics (e.g., current-voltage relations, current activation kinetics, Zn 2+ -sensitivity). When the intracellular pH of cells was alkalinized with NH 4 Cl, rates of intracellular acidification were significantly higher in Nox1 3T3 compared to mock 3T3. Nox1 3T3 showed a time course of acidification that followed a double exponential function with a fast and a slow component of, on average, τ = 165 s and 1780 s, whereas mock 3T3 showed only a single slow τ of 1560 s. Expression of Nox1 also caused cells to acidify the extracellular medium at higher rates than control cells; Nox1 3T3 released 96 ± 19 fmole·h -1 ·cell -1 of acid equivalents compared to 19 ± 12 fmole·h -1 ·cell -1 in mock 3T3. These data show that expression of Nox1 results in a mechanism that has the capacity to rapidly acidify the cytosol and generate significant amounts of acid. No significant effect of Nox1 expression on the plasma membrane H + conductance was found.

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A Ca2+-activated NADPH Oxidase in Testis, Spleen, and Lymph Nodes

Cited by 540 publications

References 58 publications

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

Expression of Nox1 in 3T3 cells increases cellular acid production but not proton conductance

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