http://atvb.ahajournals.org/content/36/2/221.extract?etoc
+ Author Affiliations
- Correspondence to Edward M. Conway, MD, PhD, Department of Medicine, Centre for Blood Research, 4306-2350 Health Sciences Mall, University of British Columbia, Vancouver BC V6T 1Z3, Canada. E-mail ed.conway@ubc.ca
Thrombomodulin is a transmembrane
glycoprotein expressed on the lumenal surface of endothelial cells,
where it maintains vascular
homeostasis via its anti-inflammatory,
anticoagulant, and anti-fibrinolytic properties. These effects of
thrombomodulin are
achieved through dynamic interactions primarily
with thrombin, protein C, thrombin activatable fibrinolysis inhibitor,
complement
components, and the proinflammatory danger
signal high mobility group box 1 (HMGB1).1
When bound to thrombomodulin, thrombin loses its
procoagulant/proinflammatory properties, while efficiently generating
activated
protein C and activated thrombin activatable
fibrinolysis inhibitor. Activated protein C is a potent anticoagulant,
anti-inflammatory
and cytoprotective protease. Activated thrombin
activatable fibrinolysis inhibitor inhibits fibrinolysis, and
inactivates
proinflammatory mediators and anaphylatoxins.
The lectin-like domain of thrombomodulin also dampens inflammation by
blocking
HMGB1 and suppressing complement activation.
Diminished expression of thrombomodulin is a feature of endothelial cell
dysfunction,
and it is a driver in the pathogenesis of
several disorders, including venous thromboembolic disease, sepsis,
disseminated
intravascular coagulation (DIC),
atherosclerosis, stroke, inflammatory arthritis and colitis, thrombotic
microangiopathies,
and diabetic nephropathy. To offset the
imbalance associated with reduced thrombomodulin, and with the aim of
preventing organ
damage, systemic administration of recombinant
forms of thrombomodulin has shown efficacy in several preclinical models
of
thrombosis and inflammation, and in humans with
DIC and sepsis.2
See accompanying article on page 361
Yang et al3
have taken a different approach to augment endothelial thrombomodulin
and limit disease, particularly focusing on thrombosis.
Going nuclear, they examined the role of 2
transcription factors, Nur77 and Nor1, members of the family of nuclear
orphan
NR4A receptors. These …
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