Arsenite stimulates plasma membrane NADPH oxidase in vascular endothelial cells

Smith, Karol R.; Klei, Linda R.; Barchowsky, Aaron

doi:10.1152/ajplung.2001.280.3.l442

Cited by 145 publications

(114 citation statements)

References 38 publications

(72 reference statements)

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“…Besides phagocytic NADPH oxidase, iAs can also stimulate nonphagocytic NADPH oxidase in endothelial cells (16,34), vascular smooth muscle cells (35), and in the human promyelocytic NB4 cell line (15); however, molecular mechanisms mediating its activation remain poorly understood. Chou et al (15) have shown that prolonged treatment of NB4 cells (9 days) with 0.75 M As 2 O 3 markedly up-regulate mRNA levels and membrane expression of p47 phox .…”

Section: Discussionmentioning

confidence: 99%

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Lemarié

Bourdonnay

Morzadec

et al. 2008

The Journal of Immunology

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Inorganic arsenic is an immunotoxic environmental contaminant to which millions of humans are chronically exposed. We recently demonstrated that human primary macrophages constituted a critical target for arsenic trioxide (As2O3), an inorganic trivalent form. To specify the effects of arsenic on macrophage phenotype, we investigated in the present study whether As2O3 could regulate the activity of NADPH oxidase, a major superoxide-generating enzymatic system in human phagocytes. Our results show that superoxide levels were significantly increased in a time-dependent manner in blood monocyte-derived macrophages treated with 1 μM As2O3 for 72 h. Concomitantly, As2O3 induced phosphorylation and membrane translocation of the NADPH oxidase subunit p47phox and it also increased translocation of Rac1 and p67phox. Apocynin, a selective inhibitor of NADPH oxidases, prevented both p47phox translocation and superoxide production. NADPH oxidase activation was preceded by phosphorylation of p38-kinase in As2O3-treated macrophages. The p38-kinase inhibitor SB-203580 prevented phosphorylation and translocation of p47phox and subsequent superoxide production. Pretreatment of macrophages with the Rho-kinase inhibitor Y-27632 was found to mimic inhibitory effects of SB-203580 and to prevent As2O3-induced phosphorylation of p38 kinase. Treatment with As2O3 also resulted in an increased secretion of the proinflammatory chemokine CCL18 that was fully inhibited by both apocynin and SB-203580. Taken together, our results demonstrate that As2O3 induced a marked activation of NADPH oxidase in human macrophages, likely through stimulation of a Rho-kinase/p38-kinase pathway, and which may contribute to some of the deleterious effects of inorganic arsenic on macrophage phenotype.

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Section: Discussionmentioning

confidence: 99%

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Lemarié

Bourdonnay

Morzadec

et al. 2008

The Journal of Immunology

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“…2 demonstrated that capillarization developed over 1-2 weeks of arsenic exposure and was greatly accelerated by arsenic compared to the natural decline in porosity seen in age matched controls. Since arsenite stimulates oxidant production by endothelial cell NAD(P)H oxidase (Smith et al, 2001), it is possible that chronic oxidant stress was responsible for arsenic-induced loss of porosity and phenotypic change in LSEC. However, if this was true, the oxidative stress would have had to be at a low level since total liver hemoxygenase-1 mRNA levels increased by less than 3-fold in following exposure to 250 ppb of arsenite for 5 wks (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

Straub

Stolz

Vin

et al. 2007

Toxicology and Applied Pharmacology

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The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration was observed in Matrigel plugs implanted in C57BL/6 mice following 5 week exposures to 5-500 ppb arsenic (Soucy et al., 2005). Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68 positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased; indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic.

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“…9). Finally, activation of Rac1 and Rac1-NADPH oxidase activity by sodium arsenite initiates a massive production of ROS in cells [61], which is followed by oxidative stress [62], mitochondrial dysfunction and an induction of mitochondrial death pathway in some melanoma lines. In addition, subsequent genotoxic stress also occurs, as well as an up-regulation of p53 protein levels and p53-dependent gene expression, such as BAX and TRAIL-R2 [39,[63][64][65], which is accompanied by an increase in apoptosis and secondary necrosis.…”

Section: Discussionmentioning

confidence: 99%

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Ivanov

Hei

2006

Experimental Cell Research

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AP-1/cJun, NF-κB and STAT3 transcription factors control expression of numerous genes, which regulate critical cell functions including proliferation, survival and apoptosis. Sodium arsenite is known to suppress both the IKK-NF-κB and JAK2-STAT3 signaling pathways and to activate the MAPK/JNK-cJun pathways, thereby committing some cancers to undergo apoptosis. Indeed, sodium arsenite is an effective drug for the treatment of acute promyelocytic leukemia with little nonspecific toxicity. Malignant melanoma is highly refractory to conventional radio-and chemotherapy. In the present study we observed strong effects of sodium arsenite treatment on upregulation of TRAILmediated apoptosis in human and mouse melanomas. Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. Furthermore, activation of cJun and suppression of NF-κB by sodium arsenite resulted in upregulation of the endogenous TRAIL-and downregulation of the cFLIP gene expression (which encodes one of the main anti-apoptotic proteins in melanomas) followed by cFLIP protein degradation and, finally, by acceleration of TRAIL-induced apoptosis. Direct suppression of cFLIP expression by cFLIP RNAi also accelerated TRAIL-induced apoptosis in these melanomas, while COX-2 suppression substantially increased levels of both TRAIL-induced and arsenite-induced apoptosis. In contrast, overexpression of permanently active AKTmyr inhibited TRAIL-mediated apoptosis via down-regulation of TRAIL-R1 levels. Finally, AKT overactivation increased melanoma survival in cell culture and dramatically accelerated growth of melanoma transplant in vivo, highlighting a role of AKT suppression for effective anti-cancer treatment.

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Arsenite stimulates plasma membrane NADPH oxidase in vascular endothelial cells

Cited by 145 publications

References 38 publications

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

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