Air pollution upregulates endothelial cell procoagulant activity via ultrafine
particle-induced oxidant signaling and tissue factor expression
#MMPMID24752501
Snow SJ
; Cheng W
; Wolberg AS
; Carraway MS
Toxicol Sci
2014[Jul]; 140
(1
): 83-93
PMID24752501
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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.
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