HR Wong, RJ Mannix, JM Rusnak, A Boota, H Zar, SC Watkins, JS Lazo and BR Pitt
Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania, USA.

We recently reported that lipopolysaccharide (LPS) induces apoptosis in cultured sheep pulmonary artery endothelial cells (SPAEC). Information about survival signals against this and other stimuli for endothelial cell apoptosis is limited to factors in the extracellular space. In other cell types, apoptosis is also affected by intracellular gene products. The heat-shock response is a highly conserved cellular stress response affording cytoprotection against a variety of cytotoxic conditions. Accordingly, we tested the hypothesis that prior induction of the heat-shock response would affect apoptosis in cultured SPAEC. Exposure of SPAEC to either heat (43 degrees C, 90 min) or sodium arsenite (100 microM, 90 min) induced expression of heat-shock protein- 70 (HSP-70). LPS (0.1 microg/ml) treatment of SPAEC induced apoptotic morphology, cell detachment, high molecular weight (> 30 kb) DNA fragmentation, and internucleosomal DNA fragmentation. Prior induction of the heat-shock response attenuated LPS-mediated apoptosis, a protective event associated with a concomitant attenuation of rapid (within minutes) LPS-stimulated superoxide anion (O2.-) generation. Subsequent experiments involving transient overexpression of HSP-70, by direct gene transfer, suggest a direct role for HSP-70 in the attenuation of LPS-mediated apoptosis. We conclude that the heat-shock response is an intracellular survival signal against LPS-mediated apoptosis, and that the protective mechanism may involve HSP-70 directly, as well as inhibition of LPS-mediated O2.- generation.

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