Submitted on February 25, 2004
Accepted on March 11, 2005
Pathologically elevated cyclic hydrostatic pressure induces CD95-mediated apoptotic cell death in vascular endothelial cells
Cornelia Hasel1*, Susanne Durr1, Anke Bauer1, Rene Heydrich1, Silke Bruederlein1, Tabe Tambi1, Umesh Bhanot1, and Peter Moller1
1 Institute of Pathology, University of Ulm, Ulm, Baden-Wuerttemberg, Germany
* To whom correspondence should be addressed. E-mail: cornelia.hasel{at}medizin.uni-ulm.de.
We describe cyclic hydrostatic pressure of 200/100 mmHg with a frequency of 85/min as a hemodynamically relevant pathologic condition enforcing apoptosis on endothelial cells setting on after 24 hrs of treatment. This went along with an increase of CD95 and CD95L surface expression, shedding of CD95L into the supernatant, cleavage of caspases 3 and 8, elevated JNK-2, c-jun, and CD95L mRNA expression. Furthermore, an increased DNA- binding activity of the AP-1 transcription factor family members FRA-1 and c-jun was observed. This activation was reduced by inhibition of JNK, which subsequently prevented elevated CD95L mRNA expression. Caspase inhibitors and a CD95L neutralizing antibody also reduced endothelial cell apoptosis. Most of the pressure-induced events were most prominent at 24 and 48 hrs. However, after 48 hrs the CD95/CD95L expression pattern switched back to CD95-/CD95L+ and the specific death rate decreased.
In conclusion, cyclic pathological hydrostatic pressure is a novel type of stress to EC rendering them susceptible to CD95/CD95L mediated auto- and/or paracrine apoptosis accompanied by up-regulation of intracellular molecules known to trigger both, apoptosis and survival.
