on August 10, 2006
Published online before print August 10, 2006, doi: 10.1161/01.ATV.0000240519.46754.9c
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Submitted on May 18, 2006
Accepted on July 31, 2006
Induction of Monocytic Tissue Factor Expression After Rewarming From Hypothermia In Vivo Is Counteracted by Heat Shock in c-Jun-Dependent Manner
Elena M. Egorina *;
sterud
From the Department of Biochemistry (E.M.E., M.A.S., J.O.O., B..), Institute of Medical Biology, and the Department of Anesthesiology (T.V.K., T.T.), Institute of Clinical Medicine, University of Tromsø, Norway.
* To whom correspondence should be addressed. E-mail: egorina{at}fagmed.uit.no.
Objective--Triggering of tissue factor (TF)-mediated blood coagulation leads to the development of disseminated intravascular coagulation during rewarming from hypothermia. We studied post-rewarming TF levels, activity, and surface redistribution, along with the regulation of TF gene transcription in mononuclear cells (MNCs) obtained from an in vivo rat model.
Methods and Results--Rewarming after a 5-hour episode of 15°C hypothermia caused an increase in TF activity, protein levels, and externalization of TF antigen in rat MNCs. This was accompanied by a dramatic elevation of c-Jun and JNK phosphorylation, and the absence of EGR-1 and NF-
B activation. To search for a stimulus to counteract c-Jun-mediated induction of TF activity in MNCs from rewarmed rats, we applied heat shock pretreatment one day before the hypothermia/rewarming experiment. This restored post-rewarming TF activity, protein levels, and surface-to-total TF ratio in rat MNCs to normothermic levels. Furthermore, in heat shock-pretreated animals, rewarming failed to increase phosphorylated c-Jun and JNK levels. We attribute this to the profound overexpression of heat shock protein 70 and inhibition of JNK.
Conclusions--MNCs respond to rewarming from hypothermia by an induction of active TF antigen. This effect is dependent on c-Jun activation and is abolished by heat shock pretreatment.