Circulation, Vol 86, 2000-2010, Copyright © 1992 by American Heart Association
S Fujii, H Sawa, JE Saffitz, CL Lucore and BE Sobel
BACKGROUND. We have shown previously that products from activated platelets
can augment synthesis of plasminogen activator inhibitor type 1 (PAI-1) in
cultured endothelial and hepatoma (Hep G2) cells in vitro and increase
plasma PAI-1 activity in vivo in rabbits. Accordingly, the effects of
activation of platelets associated with thrombosis and thrombolysis in vivo
on plasma PAI-1 activity and expression of the PAI- 1 gene in endothelium,
liver, and other organs were characterized. METHODS AND RESULTS.
Endothelial injury giving rise to platelet-rich thrombi was induced with
electrical stimulation in carotid arteries in rabbits. Clot lysis and
recanalization were induced subsequently with intravenous tissue-type
plasminogen activator (t-PA) and verified with Doppler flow probes. Plasma
PAI-1 activity (mean +/- SD) increased from 6 +/- 2 arbitrary units (AU)/ml
to 129 +/- 48 AU/ml (n = 15) within several hours after recanalization.
When t-PA had failed to induce recanalization, the increase was much less
(from 7 +/- 2 to 42 +/- 23 AU/ml, n = 11). To define mechanisms responsible
for these changes, PAI- 1 messenger RNA (mRNA) was evaluated by Northern
blot analysis and localized in tissues by in situ hybridization. Strong and
consistent induction of PAI-1 mRNA was evident in aorta, heart, and liver
of animals subjected to thrombosis (twofold to threefold increases compared
with values in controls), particularly in those in which thrombolysis had
been induced (fourfold to sixfold). After thrombolysis, an intense, PAI-1
mRNA-specific signal was detected in endothelium of aorta, liver, and
heart, with less intense signals in endothelium of lung, adrenals, and
kidneys. CONCLUSIONS. The increases in plasma PAI-1 activity follow a
preceding increase in endothelial cell expression of the PAI-1 gene as
reflected by PAI-1 mRNA levels. Thus, increased synthesis of endothelial
cell PAI-1 after thrombosis and thrombolysis may attenuate endogenous
fibrinolysis early after coronary thrombolysis, thereby potentiating early,
thrombotic reocclusion.
ARTICLES
Induction of endothelial cell expression of the plasminogen activator inhibitor type 1 gene by thrombosis in vivo
Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110.
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