© 2000 American Heart Association, Inc.
Molecular Medicine |
Estrogens and Glucocorticoids Inhibit Endothelial Vascular Cell Adhesion Molecule-1 Expression by Different Transcriptional Mechanisms
From the Scuola Superiore di Studi e di Perfezionamento "S. Anna" (T.S.), Pisa; Department of Reproductive Medicine and Child Development (T.S., A.R.G.) and Cellular and Developmental Biology Division (G. Barsacchi), University of Pisa, Italy; and CNR Institute of Clinical Physiology (S.M., G. Basta, R.D.C.), Pisa, Italy, and Cardiovascular Division (T.S., J.K.L.), Brigham and Women’s Hospital, Boston, Mass.
Correspondence to James K. Liao, MD, Vascular Medicine Unit, Department of Medicine, 221 Longwood Ave, LMRC-322, Boston, MA 02115. E-mail jliao{at}rics.bwh.harvard.edu
Abstract—The antiatherogenic
effect of estrogen is mediated, in part, by inhibitory
effects on endothelial vascular cell adhesion
molecule-1 (VCAM-1) expression. To determine the mechanism by which
estrogen regulates VCAM-1 expression, we compared the effect of
17ß-estradiol (E2) and of the glucocorticoid
dexamethasone (Dex) on lipopolysaccharide
(LPS)–induced VCAM-1 expression in human endothelial
cells. E2 decreased LPS-induced VCAM-1 mRNA and protein
expression to a greater extent than Dex. Dex, but not E2,
stabilized VCAM-1 mRNA. This correlated with inhibition of monocytoid
U937 cell adhesion to endothelial cells. Transfection
of endothelial cells with a functional VCAM-1 promoter
construct showed that E2 inhibited LPS-induced VCAM-1 gene
transcription more potently than did Dex. However, using a truncated
construct containing only the nuclear factor-
B (NF-B)–responsive
elements but lacking the consensus sequences for activator
protein-1 (AP-1) and GATA, E2 and Dex had similar
inhibitory effects. Consistently, gel-shift assays
showed that E2 and Dex comparably inhibit LPS-induced
activation of NF-B, whereas E2 inhibited LPS-induced
activation of AP-1 and GATA to a greater extent than Dex.
E2 inhibition of NF-B after LPS treatment was associated
with decreased inhibitor B (IB) kinase
activity and with a stabilization of the NF-B
inhibitor IB
. These results indicate that
E2 decreases VCAM-1 gene expression through the inhibition
of NF-B, AP-1, and GATA and suggest novel mechanisms for the
antiatherogenic effect of estrogen on the vascular wall.
(Circ Res. 2000;87:19-25.)
Key Words: estrogen • glucocorticoid • endothelial-leukocyte adhesion molecules • nuclear factor-B • endothelial cells
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