Low Levels of Arsenic Trioxide Stimulate Proliferative Signals in Primary Vascular Cells without Activating Stress Effector Pathways

Barchowsky, Aaron; Roussel, Robert R.; Klei, Linda R.; James, Philip E.; Ganju, Neema; Smith, Karol R.; Dudek, Edward J.

doi:10.1006/taap.1999.8723

Cited by 169 publications

(100 citation statements)

References 47 publications

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“…In this study, no enhanced activation of MAP kinase pathways was observed in association with arsenic exposure. Relatively low levels of arsenic may have different modes of action, as proposed by Barchowsky (Barchowsky et al 1999). MAP kinase pathways may not be activated in the study subjects with relatively low-level arsenic exposure, such as those derived from drinking water.…”

Section: Discussionmentioning

confidence: 98%

Gene Expression of Inflammatory Molecules in Circulating Lymphocytes from Arsenic-Exposed Human Subjects

Wu¹,

Chiou²,

Ho³

et al. 2008

Environ. Health Perspect.

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Section: Discussionmentioning

confidence: 98%

Gene Expression of Inflammatory Molecules in Circulating Lymphocytes from Arsenic-Exposed Human Subjects

Wu¹,

Chiou²,

Ho³

et al. 2008

Environ. Health Perspect.

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“…In vivo, high doses of arsenic affect all cells in the liver and promote a significant amount of apoptosis in hepatocytes (Bashir et al, 2006). High doses of arsenic (>5 μM) are known to be toxic to endothelial cells (Barchowsky et al, 1996;Barchowsky et al, 1999;Kao et al, 2003;Roboz et al, 2000) and it is possible that high dose exposures elicit multiple mechanisms for toxicity that mask the pathogenic mechanisms mediating liver diseases in response to environmentally relevant arsenic exposures. In contrast, the current study investigated effects of a relevant ad libitum ingestion of drinking water containing an arsenic level that was near the threshold for observing significant liver disease in humans (250 ppb = ∼ 0.7-.9 μg/mouse/ day for 5 weeks; human equivalent ∼ 32 μg/day for 3.75 years).…”

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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“…Stress kinases such as p38 and c-Jun aminoterminal kinase (JNK) could also potentially be involved in the observed effects of As (III). Barchowsky et al, (1999) showed that high levels of As(III) can induce cellular stress and activate stress kinases including p38. On the other hand, lower concentrations have been shown to induce DNA synthesis and reactive oxygen species (Barchowsky et al, 1996) without activating stress kinases (Barchowsky et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Barchowsky et al, (1999) showed that high levels of As(III) can induce cellular stress and activate stress kinases including p38. On the other hand, lower concentrations have been shown to induce DNA synthesis and reactive oxygen species (Barchowsky et al, 1996) without activating stress kinases (Barchowsky et al, 1999). The role of these alternative pathways in endothelial arsenic toxicity is the subject for future investigations.…”

Section: Discussionmentioning

confidence: 99%

Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite—Potential mechanism in the development of atherosclerosis

Pereira

Coffin

Beall

2007

Toxicology and Applied Pharmacology

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Arsenic exposure has been shown to exacerbate atherosclerosis, beginning with activation of the endothelium that lines the vessel wall. Endothelial barrier integrity is maintained by proteins of the adherens junction (AJ) such as vascular endothelial cadherin (VE-cadherin) and β-catenin and their association with the actin cytoskeleton. In the present study, human aortic endothelial cells (HAECs) were exposed to 1, 5 and 10 μM sodium arsenite [As(III)] for 1, 6, 12 and 24 h, and the effects on endothelial barrier integrity were determined. Immunofluorescence studies revealed formation of actin stress fibers and non-uniform VE-cadherin and β-catenin staining at cell-cell junctions that were concentration and time-dependent. Intercellular gaps were observed with a measured increase in endothelial permeability. In addition, concentration-dependent increases in tyrosine phosphorylation (PY) of β-catenin and activation of protein kinase Cα (PKCα) were observed. Inhibition of PKCα restored VE-cadherin and β-catenin staining at cell-cell junctions and abolished the As(III) induced formation of actin stress fibers and intercellular gaps. Endothelial permeability and PY of β-catenin were also reduced to basal levels. These results demonstrate that As(III) induces activation of PKCα, which leads to increased PY of β-catenin downstream of PKCα activation. Phosphorylation of β-catenin plausibly severs the association of VE-cadherin and β-catenin, which along with formation of actin stress fibers, results in intercellular gap formation and increased endothelial permeability. To the best of our knowledge, this is the first report demonstrating that As(III) causes a loss of endothelial monolayer integrity, which potentially could contribute to the development of atherosclerosis.

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Low Levels of Arsenic Trioxide Stimulate Proliferative Signals in Primary Vascular Cells without Activating Stress Effector Pathways

Cited by 169 publications

References 47 publications

Gene Expression of Inflammatory Molecules in Circulating Lymphocytes from Arsenic-Exposed Human Subjects

Gene Expression of Inflammatory Molecules in Circulating Lymphocytes from Arsenic-Exposed Human Subjects

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

Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite—Potential mechanism in the development of atherosclerosis

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