(Circulation. 2000;102:2990.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Antioxidant Effect of Estrogen on Cytomegalovirus-Induced Gene Expression in Coronary Artery Smooth Muscle Cells
From the Cardiology Branch (E.S., R.O.C.) and Pathology Section (Z.-X.Y., K.T., V.J.F.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Edith Speir, National Institutes of Health, Building 10, Room 7B15, 10 Center Dr MSC-1650, Bethesda, MD 20892-1650. E-mail speire{at}nih.gov
Background—Pathogens infecting the arterial wall with resultant inflammation may contribute to atherogenesis. Human coronary artery smooth muscle cells (SMCs) infected with human cytomegalovirus (CMV) demonstrate a rapid increase in reactive oxygen species (ROSs), with activation of genes involved in viral replication and inflammation. Because estrogen appears to have antioxidant properties, we wished to determine whether this hormone attenuates SMC responses to CMV infection.
Methods and Results—Using confocal microscopy and an
intracellular fluorescent dye activated by ROSs, we
found that 17ß-estradiol (0.1 to 10 nmol/L) and its stereoisomer
17
-estradiol (which has low affinity for the estrogen receptor)
dose-dependently inhibited ROS generation in CMV-infected SMCs. These
effects were not blocked by the estrogen receptor inhibitor
ICI 182,780. 3-Methoxyestrone, which lacks the phenolic hydroxyl group,
did not interfere with ROS generation. We found that 17ß-estradiol
and 17-estradiol, but not 3-methoxyestrone, prevented binding of
nuclear factor (NF)-
B to DNA. Furthermore, in SMCs transfected with
the reporter constructs 3XB-CAT, MIEP-CAT, or ICAM-CAT,
cotransfection with a CMV-IE72 expression plasmid caused promoter and
CAT activation. Treatment with 17ß-estradiol and 17-estradiol, but
not 3-methoxyestrone, inhibited CAT activity and, in CMV-infected SMCs,
prevented IE72 and ICAM-1 protein expression and cytopathic
effects.
Conclusions—These findings indicate that estrogen molecules with
an A-ring hydroxyl group have estrogen receptor–independent anti-CMV
effects at physiological concentrations by
inhibiting ROS generation, NF-B activation, NF-B–dependent
transcription, and viral replication. To the extent that chronic
infection of the vascular wall with CMV contributes to atherogenesis,
these antioxidant actions of estrogen may be of therapeutic importance.
Key Words: atherosclerosis • viruses • hormones • antioxidants • adhesion molecules
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