Induction of human endothelial cell apoptosis requires both heat
shock and oxidative stress responses.
Wang, Jiang Huai, H. Paul Redmond, R. William G. Watson, and David
Bouchier-Hayes.
The Royal College of Surgeons in Ireland, Department of Surgery,
Beaumont Hospital, Dublin 9, Ireland
APStracts 3:0410C, 1996.
Endothelial cell (EC) death may play an important role in the
development of increased vascular permeability and capillary leak
syndrome during systemic inflammatory response syndrome (SIRS).
However, the mode of EC death and the mechanisms involved remain
unclear. In this study we employed the proinflammatory mediators,
lipopolysaccharide (LPS) and tumor necrosis factor-[alpha] (TNF
-[alpha]), the chemical reagent, sodium arsenite, and heat shock to
trigger the stress gene responses. Human ECs were used as surrogates
of the microvasculature in order to test the hypothesis that the
induction of the heat shock response and the oxidative stress
response might combine to induce apoptosis rather than necrosis in
human ECs. Sodium arsenite at a dose range of 80-320 [mu]M, which
induced both heat shock protein 72-kDa (HSP-72) expression and
reactive oxygen intermediate (ROI) generation in ECs, resulted in EC
apoptosis. TNF-[alpha] alone (5-75 ng/ml) increased EC ROI
generation, but did not induce EC apoptosis. Heat shock alone (42oC,
45 min) or sodium arsenite (40 [mu]M) alone, each of which induced
HSP-72 expression, did not resulted in EC apoptosis. However, the
combination of TNF-[alpha] with heat shock or 40 [mu]M sodium
arsenite led to EC apoptosis as both HSP-72 expression and ROI were
induced. Furthermore, sodium arsenite (80 [mu]M) in the presence of
antioxidants failed to induce EC apoptosis. Apoptotic ECs also
exhibited functional disturbances as represented by the depression of
intercellular adhesion molecule-1 (ICAM-1) expression, as well as the
disruption of EC monolayer integrity. These results indicate that the
simultaneous induction of both a heat shock response and an oxidative
stress response is responsible for human EC apoptosis.
Received 14 May 1996; accepted in final form 5 December 1996.
APS Manuscript Number C266-6.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996