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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1628.)
© 2004 American Heart Association, Inc.

Vascular Biology

Estrogen, Heat Shock Proteins, and NFB in Human Vascular Endothelium

Karyn L. Hamilton; F.N. Mbai; S. Gupta; A.A. Knowlton

From the University of California (F.N.M., S.G., A.A.K.), Davis, Calif; Sacramento VA Medical Center (A.A.K.), Sacramento, Calif; and Baylor College of Medicine (K.L.H.), Houston, Tex.

Correspondence to Dr A.A. Knowlton, Cardiovascular Division, TB 172, University of California, Davis, One Shields Avenue, Davis, CA 95616. E-mail aaknowlton{at}ucdavis.edu

Background— We hypothesized that estrogen would increase HSP72 in human coronary artery endothelial cells (HCAEC), and that these would be more sensitive to estrogen than our previous observations in myocytes.

Methods and Results— HCAEC were treated with 17ß-estradiol or tamoxifen, ranging from physiological to pharmacological(1 nM to 10 µmol/L) for either 24 hours (early) or 7 days (chronic). HSP expression was assessed by Western blots. Both early and chronic 17ß-estradiol and tamoxifen increased HSP72. Electromobility shift assays (EMSA) showed activation of HSF-1 with early, but not chronic, 17ß-estradiol. 17ß-Estradiol activated NFB within 10 minutes, and the ER- selective inhibitor, ICI 182 780, abolished this effect. Transcription factor decoys containing the heat shock element blocked HSP72 induction. Estrogen pretreatment decreased lactate dehydrogenase release with hypoxia. This protective effect persisted despite blockade of HSF-1 by decoys. However, an NF-B decoy prevented the increase in HSP72 and abolished the estrogen-associated protection during hypoxia.

Conclusions— 17ß-Estradiol upregulates HSP72 early and chronically via different mechanisms in HCAEC, and provides cytoprotection during hypoxia, independent of HSP72 induction. NF-B mediates the early increase in HSP72, suggesting that estrogen activates NF-B via a nongenomic, receptor-dependent mechanism, and this leads to activation of HSF-1. Activation of NF-B was critical for estrogen-associated protection. Further studies are needed to elucidate the involved signaling pathways.

We hypothesized that estrogen would increase HSP72 in human coronary artery endothelial cells (HCAEC). Both early and chronic treatment increased HSP72. EMSA showed activation of HSF-1 with early, but not chronic, 17ß-estradiol. Transcription factor decoys blocked estrogen-related HSP72 induction. Estrogen decreased LDH release with hypoxia. An NF-B decoy blocked the HSP72 increase and estrogen-associated protection.

Key Words: estrogen • endothelium • signal transduction • hypoxia • HSP72

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