Microvascular Dysfunction with Increased Vascular Leakage Response in Mice Systemically Exposed to Arsenic

Chen, Shih‐Chieh; Huang, Shin-Yin; Lu, Chi‐Yu; Hsu, Ya-Hung; Wang, Dean-Chuan

doi:10.1007/s12012-014-9246-2

Cited by 6 publications

(10 citation statements)

References 22 publications

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“…Our data also showed that systemic arsenic exposure markedly decreased aortic SMC area in absence of aortic luminal fatty streaks, accompanied by a significantly decreased SM22 level in wild-type ICR mice on a regular diet. Recent studies indicate the presence of microvascular dysfunction with increased vascular leakage in response to inflammatory stimuli in mice systemically exposed to arsenic [18,19]. Thus, our data showed arsenic-mediated alterations of vascular structure in wild-type mice, suggesting an impact of arsenic on vascular structure independent of plasma hyperlipidemia.…”

Section: Discussionsupporting

confidence: 65%

“…A previous study suggested that arsenicinduced endothelial dysfunction occurs through oxidative stress events that lead to atherosclerosis in animal models [17]. Recent studies indicate that microvascular dysfunction and increased vascular leakage occur in response to inflammatory stimuli following systemic arsenic exposure, even in wild-type mice [18,19]. In the present study, we examined whether systemic arsenic exposure induced morphological and biochemical alterations of SMCs in the aorta of ICR mice.…”

Section: Introductionmentioning

confidence: 87%

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Aortic smooth muscle cell alterations in mice systemically exposed to arsenic

et al. 2015

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Previous epidemiological studies showed that chronic arsenic exposure is related to increased cardiovascular disease incidence. The detailed biochemical mechanisms by which arsenic exerts its effects remain unknown. Vascular disease progression is characterized by smooth muscle cell (SMC) phenotypic switching, vessel wall reorganization, and platelet-derived growth factor (PDGF) production. The objective of this study was to examine early biochemical and structural changes in the aortas of ICR mice systemically exposed to arsenic. Animals were fed sodium arsenite (20 mg/kg) via gavage 5 days/week or Milli-Q water only (control) for 8 weeks. Aortic proteins were subjected to two-dimensional (2-D) differential gel electrophoresis and proteomic studies. Two 2-D gel protein spots were identified as the same protein, smooth muscle (SM)22α, using proteomics. SM22α and Rho kinase 2 gene and protein expression were significantly decreased in the aortic tissue of arsenic-exposed mice compared with that of control mice. No atherosclerotic lesion formation or tissue injury was detected in the aortic wall of either the arsenic-fed or the control group. However, the percent (%) SMC area of the aortic wall was significantly decreased in arsenic-fed mice compared with that in control mice. Additionally, the expression levels of PDGF-BB and early growth response-1 (Egr-1) were significantly higher in the arsenic group than that in the control group. These findings reveal biochemical alterations of SM22α, PDGF, and Egr-1 in conjunction with decreased SMC area in the aortic wall of arsenic-fed mice. Arsenic may initiate aortic SMC alterations that subsequently lead to vascular dysfunction.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 87%

Aortic smooth muscle cell alterations in mice systemically exposed to arsenic

et al. 2015

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“…Chronic exposure to 200 or 1000 ppb iAs in drinking water also showed development of atherosclerotic plaques in the macrovasculature of ApoE-/- mice [20] . Mice administered 20 mg/kg of sodium arsenite in water showed increased vascular leakage [5] . At a similar dose, iAs had anti-angiogenic activity in solid tumor models by decreasing expression of vascular endothelial growth factor (VEGF) [34] .…”

Section: Introductionmentioning

confidence: 97%

“…Animal studies have produced conflicting results [5] , [6] , [28] . In FVB female mice, chronic exposure to 100 ppb iAs III in drinking water for 22 weeks was shown to induce hypertension and cardiac hypertrophy [25] .…”

Section: Introductionmentioning

confidence: 99%

Effect of trivalent arsenicals on cell proliferation in mouse and human microvascular endothelial cells

et al. 2015

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Chronic exposure to high levels of inorganic arsenic (iAs) has been associated with cancerous and non-cancerous health effects, including cardiovascular effects. However, the mechanism for a presumed toxic effect of arsenic on vascular tissue is not clear. Our working hypothesis is that inorganic trivalent arsenic and its methylated metabolites react with cysteine-containing cellular proteins and alter their function leading to adverse events such as cytotoxicity or proliferation. In this study, human microvascular endothelial cells (HMEC1) and mouse microvascular endothelial cells (MFP-MVEC) were exposed to arsenite (iAsIII), monomethylarsonous acid (MMAIII), or dimethylarsinous acid (DMAIII) for 72 h to evaluate cytotoxicity, and for 24, 48 or 72 h to evaluate cell proliferation. Both cell lines showed similar LC50 values, from 0.1 to 2.4 μM, for all three trivalent arsenicals. The endothelial cells treated with1 nM to 1 μM concentrations of the three trivalent arsenicals did not show increased cell proliferation at 24, 48 or 72 h or increased rate of proliferation at 72 h of exposure. Overall, cytotoxicity of trivalent arsenicals to microvascular endothelial cells is similar to their cytotoxicity to epithelial cells, and that these compounds are not mitogenic.

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“…Because ~140 million people worldwide are at risk of exposure to excessive levels of naturally occurring As in well water and groundwater [ 1 ], exposure of As in drinking water is a serious public health problem. Several studies have shown that chronic exposure to As is associated with increased incidence of several human diseases including cardiovascular disease [ 2 ]. Although the molecular mechanism in which As causes vascular disease has not yet been defined, it is well accepted that increased toxicity of vessels cells resulting from As-induced reactive oxygen species (ROS) is significant.…”

Section: Introductionmentioning

confidence: 99%

The Green Tea Component (-)-Epigallocatechin-3-Gallate Sensitizes Primary Endothelial Cells to Arsenite-Induced Apoptosis by Decreasing c-Jun N-Terminal Kinase-Mediated Catalase Activity

Kim

Choi²,

Lee

et al. 2015

PLoS ONE

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The green tea component (-)-epigallocatechin-3-gallate (EGCG) has been shown to sensitize many different types of cancer cells to anticancer drug-induced apoptosis, although it protects against non-cancerous primary cells against toxicity from certain conditions such as exposure to arsenic (As) or ultraviolet irradiation. Here, we found that EGCG promotes As-induced toxicity of primary-cultured bovine aortic endothelial cells (BAEC) at doses in which treatment with each chemical alone had no such effect. Increased cell toxicity was accompanied by an increased condensed chromatin pattern and fragmented nuclei, cleaved poly(ADP-ribose) polymerase (PARP), activity of the pro-apoptotic enzymes caspases 3, 8 and 9, and Bax translocation into mitochondria, suggesting the involvement of an apoptotic signaling pathway. Fluorescence activated cell sorting analysis revealed that compared with EGCG or As alone, combined EGCG and As (EGCG/As) treatment significantly induced production of reactive oxygen species (ROS), which was accompanied by decreased catalase activity and increased lipid peroxidation. Pretreatment with N-acetyl-L-cysteine or catalase reversed EGCG/As-induced caspase activation and EC toxicity. EGCG/As also increased the phosphorylation of c-Jun N-terminal kinase (JNK), which was not reversed by catalase. However, pretreatment with the JNK inhibitor SP600125 reversed all of the observed effects of EGCG/As, suggesting that JNK may be the most upstream protein examined in this study. Finally, we also found that all the observed effects by EGCG/As are true for other types of EC tested. In conclusion, this is firstly to show that EGCG sensitizes non-cancerous EC to As-induced toxicity through ROS-mediated apoptosis, which was attributed at least in part to a JNK-activated decrease in catalase activity.

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Microvascular Dysfunction with Increased Vascular Leakage Response in Mice Systemically Exposed to Arsenic

Cited by 6 publications

References 22 publications

Aortic smooth muscle cell alterations in mice systemically exposed to arsenic

Aortic smooth muscle cell alterations in mice systemically exposed to arsenic

Effect of trivalent arsenicals on cell proliferation in mouse and human microvascular endothelial cells

The Green Tea Component (-)-Epigallocatechin-3-Gallate Sensitizes Primary Endothelial Cells to Arsenite-Induced Apoptosis by Decreasing c-Jun N-Terminal Kinase-Mediated Catalase Activity

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