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Up-regulation of tissue factor in human pulmonary artery endothelial cells after ultrafine particle exposure.

ABSTRACT: BACKGROUND: Epidemiology studies have linked exposure to pollutant particles to increased cardiovascular mortality and morbidity, but the mechanisms remain unknown. OBJECTIVES: We tested the hypothesis that the ultrafine fraction of ambient pollutant particles would cause endothelial cell dysfunction. METHODS: We profiled gene expression of human pulmonary artery endothelial cells (HPAEC) exposed to ultrafine particles (UFPs; 100 microg/mL) from Chapel Hill, North Carolina, or vehicle for 4 hr with Affymetrix HG U133 Plus 2.0 chips (n = 4 each). RESULTS: We found 320 up-regulated genes and 106 down-regulated genes (p < 0.01, 5% false discovery rate). We noted up-regulation of genes related to coagulation [tissue factor (F3) and coagulation factor II receptor-like 2 (F2RL2)] and differential regulation of genes related to F3 signaling (FOS, JUN, and NFKBIA). Results of quantitative polymerase chain reaction show a significant up-regulation of F3 after 10 and 100 microg/mLUFP exposures. Additionally, the water-soluble fractions of UFPs were sufficient to induce the expression of F3, F2RL2, and heme oxygenase 1 (HMOX1). Treatment of HPAEC with UFPs for 16 hr increased the release of interleukin (IL)-6 and IL-8. Pretreatment of HPAEC with a blocking antibody against F3 attenuated IL-6 and IL-8 release by 30 and 70%, respectively. CONCLUSIONS: Using gene profiling, we discovered that UFPs may induce vascular endothelial cells to express genes related to clotting. These results indicate that PM may cause adverse cardiovascular health effects by activating coagulation-inflammation circuitry.

SUBMITTER: Karoly ED

PROVIDER: S-EPMC1852686 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Up-regulation of tissue factor in human pulmonary artery endothelial cells after ultrafine particle exposure.

Karoly Edward D ED Li Zhuowei Z Dailey Lisa A LA Hyseni Xhevahire X Huang Yuh-Chin T YC

Environmental health perspectives 20070108 4

<h4>Background</h4>Epidemiology studies have linked exposure to pollutant particles to increased cardiovascular mortality and morbidity, but the mechanisms remain unknown.<h4>Objectives</h4>We tested the hypothesis that the ultrafine fraction of ambient pollutant particles would cause endothelial cell dysfunction.<h4>Methods</h4>We profiled gene expression of human pulmonary artery endothelial cells (HPAEC) exposed to ultrafine particles (UFPs; 100 microg/mL) from Chapel Hill, North Carolina, or ...[more]

PMID: 17450221

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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) (100Î¼g/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. Experiment Overall Design: Human pulmonary artery endothelial cell cultures were treated with Chapel Hill Ultrafine particles or with vehicle control for 4h. 4 bological replicates each for treatment (100ug/ml) and control. 8 affy chips total.

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

Dataset Information

Up-regulation of tissue factor in human pulmonary artery endothelial cells after ultrafine particle exposure.

Publications

Up-regulation of tissue factor in human pulmonary artery endothelial cells after ultrafine particle exposure.

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