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Air Pollution Upregulates Endothelial Cell Procoagulant Activity Via Ultrafine Particle-Induced Oxidant Signaling and Tissue Factor Expression
Citation:
Snow, S., W. Cheng, A. Wolberg, AND Martha Sue Carraway. Air Pollution Upregulates Endothelial Cell Procoagulant Activity Via Ultrafine Particle-Induced Oxidant Signaling and Tissue Factor Expression. Gary W. Miller, Editor in Chief (ed.), TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 140(1):83-93, (2014).
Impact/Purpose:
Here we report that the soluble components of UF PM induce a procoagulant phenotype in endothelial cells, supporting faster onset of thrombin generation and fibrin clot formation, and that these activities are driven by upregulation of TF. We further show that this increase in TF mRNA is regulated by increased ROS production from NOX-4, and can be attenuated by treatment of cells with antioxidants or NOX-4 inhibition. These novel findings provide mechanistic insight into the enhanced thrombosis and endothelial dysfunction that underly increased risk for CV morbidity and mortality associated with air pollution exposure.
Description:
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 H202 production following soluble UF exposure and identified the enzymatic source. Soluble UF exposure increased endothelial H202 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 H202, 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.