Citation:

KAROLY, E., Z. LI, L. A. DAILEY, J. HYSENI, AND Y. T. HUANG. UPREGULATION OF TISSUE FACTOR IN HUMAN ENDOTHELIAL CELLS FOLLOWING ULTRAFINE PARTICLE EXPOSURE. Presented at The role of air polutants in cardiovascular disease, meeting, sponsored by NHLBI/NIEHS, Research Triangle Park, NC, October 12 - 13, 2006.

Description:

Epidemiology studies have linked the exposure to air pollutant particles with increased cardiovascular mortality and morbidity, but the mechanisms remain unknown. In our laboratory we have tested the hypothesis that the ultrafine fraction of ambient pollutant particles would cause endothelial cell dysfunction. We profiled gene expression of human pulmonary artery endothelial cells (HPAEC) exposed to ultrafine Chapel Hill particles (UFP) (100 ¿g/ml) or vehicle control for 4 hours with Affymetrix HG U133 Plus 2.0 chips. Microarray data analysis identified 426 unique genes differentially expressed following UFP exposure for 4 hours in HPAEC (p<0.01, 5% false discovery rate). Among these were genes related to the coagulation-inflammation circuitry, including upregulation of F3 (tissue factor gene), F2RL2 (PAR3 gene), IL-6 and IL-8 and downregulation of F8A1. There were also a group of genes that were involved in the pathogenesis of vascular disease, including those associated with clotting independent signaling of F3 (FOS, JUN, NFKBIA), HMOX1 and genes related to the CXC family of chemokines (MCP-1, IL-8, CXCL1, CXCL2 [MIP-2α], CXCL3 [MIP-2β] and CXCR4). Real time-PCR results verified our array results and also showed a significant upregulation of F3 following 10 and 100 µg /ml UFP exposures. Western blot analysis also identified elevated protein expression of TF following UFP exposures. HPAEC were also exposed to water-soluble and -insoluble fractions of UFP for 2 and 24h hours. The water-soluble fraction of UFP was found to be sufficient to induce the expression of F3, F2RL2 and heme oxygenase 1 (HMOX1). Our studies also found that treatment of HPAEC with UFP for 16 hours increased the release of IL-6 and IL-8. However, pretreatment of HPAEC with a blocking antibody against F3 attenuated IL-6 and IL-8 release by 30% and 70% respectively. In summary, using gene profiling, we found that UFP induced genes that have been implicated in the pathogenesis of vascular disease, including those linked to clotting dependent and independent signaling pathways mediated by TF as well as the CXC family of chemokines. These results support our hypotheses that UFP exposure may induce endothelial cell dysfunction leading to vascular changes and suggest that exposure to high concentrations of UFP may be considered a risk factor for the development of cardiovascular disease. (Abstract does not reflect USEPA policy).

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