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Air pollution upregulates endothelial cell procoagulant activity via ultrafine particle-induced oxidant signaling and tissue factor expression.

ABSTRACT: Air pollution exposure is associated with cardiovascular events triggered by clot formation. Endothelial activation and initiation of coagulation are pathophysiological mechanisms that could link inhaled air pollutants to vascular events. Here we investigated the underlying mechanisms of increased endothelial cell procoagulant activity following exposure to soluble components of ultrafine particles (soluble UF). Human coronary artery endothelial cells (HCAEC) were exposed to soluble UF and assessed for their ability to trigger procoagulant activity in platelet-free plasma. Exposed HCAEC triggered earlier thrombin generation and faster fibrin clot formation, which was abolished by an anti-tissue factor (TF) antibody, indicating TF-dependent effects. Soluble UF exposure increased TF mRNA expression without compensatory increases in key anticoagulant proteins. To identify early events that regulate TF expression, we measured endothelial H2O2 production following soluble UF exposure and identified the enzymatic source. Soluble UF exposure increased endothelial H2O2 production, and antioxidants attenuated UF-induced upregulation of TF, linking the procoagulant responses to reactive oxygen species (ROS) formation. Chemical inhibitors and RNA silencing showed that NOX-4, an important endothelial source of H2O2, was involved in UF-induced upregulation of TF mRNA. These data indicate that soluble UF exposure induces endothelial cell procoagulant activity, which involves de novo TF synthesis, ROS production, and the NOX-4 enzyme. These findings provide mechanistic insight into the adverse cardiovascular effects associated with air pollution exposure.

SUBMITTER: Snow SJ

PROVIDER: S-EPMC4133589 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Air pollution upregulates endothelial cell procoagulant activity via ultrafine particle-induced oxidant signaling and tissue factor expression.

Snow S J SJ Cheng W W Wolberg A S AS Carraway M S MS

Toxicological sciences : an official journal of the Society of Toxicology 20140420 1

Air pollution exposure is associated with cardiovascular events triggered by clot formation. Endothelial activation and initiation of coagulation are pathophysiological mechanisms that could link inhaled air pollutants to vascular events. Here we investigated the underlying mechanisms of increased endothelial cell procoagulant activity following exposure to soluble components of ultrafine particles (soluble UF). Human coronary artery endothelial cells (HCAEC) were exposed to soluble UF and asses ...[more]

PMID: 24752501

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Project description:Epidemiology studies have linked exposure to pollutant particles to increased cardiovascular mortality and morbidity, however, the mechanism remains unknown. In this study, we hypothesized that the ultrafine fraction of ambient pollutant particles would cause endothelial cells dysfunction. We profiled gene expression of human pulmonary artery endothelial cells (HPAEC) exposed to ultrafine Chapel Hill particles (UFP) (100μg/ml) or vehicle for 4h with Affymetrix HG U133 Plus 2.0 chips (N = 4 each). Using an unpaired t-test (p <0.01, 5% false discovery rate) we found 426 unique genes to be differentially expressed with 320 upregulated genes and 106 downregulated genes. Among these genes, we noted upregulation of genes related to coagulation-inflammation circuitry including tissue factor (F3), coagulation factor II receptor-like 2 (F2RL2, PAR3), interleukin (IL)-6 and IL-8. Upregulation of these genes were independently confirmed by RT-PCR and/or protein release. Genes related to the CXC chemokine family that have been implicated in the pathogenesis of vascular disease were upregulated, including MCP-1 (2.60 fold), IL-8 (2.47 fold), CXCL1 (1.41 fold), CXCL2 (1.95 fold), CXCL3 (2.28 fold) and CXCR4 (1.30 fold). In addition, genes related to clotting independent signaling of F3 were also differentially expressed, including FOS, JUN and NFKBIA. Treatment of HPAEC with UFP for 16 hours increased the release of IL6 and IL8 by 1.9-fold and 1.8-fold respectively. Pretreatment of HPAEC with a blocking antibody against F3 attenuated IL6 and IL8 release by 30% and 70% respectively. Thus using gene profiling, we uncovered that UFP may induce vascular endothelial cells to express genes related to clotting and angiogenesis. These results provide a novel hypothesis that PM may cause cardiovascular adverse health effects via induction of tissue factor in vascular endothelial cells which then triggers clotting dependent and independent downstream signaling. Keywords: particle treatment

Project description:Epidemiological studies have reported associations of air pollution exposures with various neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit and schizophrenia, all of which are male-biased in prevalence. Our studies of early postnatal exposure of mice to the ultrafine particle (UFP) component of air pollution, considered the most reactive component, provide support for these epidemiological associations, demonstrating male-specific or male-biased neuropathological changes and cognitive and impulsivity deficits consistent with these disorders. Since these neurodevelopmental disorders also include altered social behavior and communication, the current study examined the ability of developmental UFP exposure to reproduce these social behavior deficits and to determine whether any observed alterations reflected changes in steroid hormone concentrations. Elevated plus maze, social conditioned place preference, and social novelty preference were examined in adult mice that had been exposed to concentrated (10-20x) ambient UFPs averaging approximately 45 ug/m3 particle mass concentrations from postnatal day (PND) 4-7 and 10-13 for 4 h/day. Changes in serum testosterone (T) and corticosterone where measured at postnatal day (P)14 and approximately P120. UFP exposure decreased serum T concentrations on PND 14 and social nose-to-nose sniff rates with novel males in adulthood, suggesting social communication deficits in unfamiliar social contexts. Decreased sniff rates were not accounted for by alterations in fear-mediated behaviors and occurred without overt deficits in social preference, recognition or communication with a familiar animal or alterations in corticosterone. Adult T serum concentrations were positively correlated with nose to nose sniff rates. Collectively, these studies confirm another feature of male-biased neurodevelopmental disorders following developmental exposures to even very low levels of UFP air pollution that could be related to alterations in sex steroid programming of brain function.

Dataset Information

Air pollution upregulates endothelial cell procoagulant activity via ultrafine particle-induced oxidant signaling and tissue factor expression.

Publications

Air pollution upregulates endothelial cell procoagulant activity via ultrafine particle-induced oxidant signaling and tissue factor expression.

Similar Datasets

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