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

Toxicol Sci. 2014 Jul;140(1):83-93. doi: 10.1093/toxsci/kfu071. Epub 2014 Apr 20.


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.

Keywords: NADPH oxidases; air pollution; reactive oxygen species; thrombin generation; tissue factor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Air Pollutants / chemistry
  • Air Pollutants / toxicity*
  • Cell Culture Techniques
  • Cell Line
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Endothelial Cells / metabolism
  • Fibrin / metabolism
  • Humans
  • NADPH Oxidase 4
  • NADPH Oxidases / metabolism
  • Oxidative Stress / drug effects*
  • Particle Size
  • Particulate Matter / chemistry
  • Particulate Matter / toxicity*
  • Reactive Oxygen Species / metabolism
  • Real-Time Polymerase Chain Reaction
  • Solubility
  • Thrombin / metabolism*
  • Thromboplastin / metabolism*


  • Air Pollutants
  • Particulate Matter
  • Reactive Oxygen Species
  • Fibrin
  • Thromboplastin
  • NADPH Oxidase 4
  • NADPH Oxidases
  • NOX4 protein, human
  • Thrombin