| Post-menopausal women have higher incidence of heart diseases compared
to pre-menopausal women, suggesting a protective role for estrogen.
The recently Women's Health Initiative (WHI) randomized controlled
trial concluded that the overall heart risk exceeded benefits from
use of combined estrogen and progestin as hormone replacement therapy
for an average of five years among healthy postmenopausal US women.
Therefore, there is an urgent need for new agents with tissue-selective
activity with no deleterious effects. In the present study, we tested
the effects on vascular tissues in vitro and in vivo of two natural
compounds derived from licorice root: glabridin, the major isoflavan,
and glabrene, an isoflavene, both demonstrated estrogen-like activities.
Similar to ESTRADIOL-17beta
(E2), glabridin (gla) stimulated DNA synthesis in human endothelial
cells (ECV-304; E304) and had a bi-phasic effect on proliferation of
human vascular smooth muscle cells (VSMC). RALOXIFENE inhibited
gla as well as E2 activities. In animal studies, both intact females
or after ovariectomy, gla similar to E2 stimulated the specific activity
of creatine kinase (CK) in aorta (Ao) and in left ventricle of the
heart (Lv). Glabrene (glb), on the other hand, had only the stimulatory
effect on DNA synthesis in vascular cells, with no inhibition by RALOXIFENE,
suggesting a different mechanism of action. To further elucidate the
mechanism of action of glb, cells were pre-incubated with glb and then
exposed to either E2 or to gla; the DNA stimulation at low doses was
unchanged but there was abolishment of the inhibition of VSMC cell
proliferation at high doses as well as inhibition of CK stimulation
by both E2 and by gla. We conclude that glb behaved differently than
E2 or gla, but similarly to RALOXIFENE,
being a partial agonist/antagonist of E2. Glabridin, on the other hand,
demonstrated only estrogenic activity. Therefore, we suggest the use
of glb with or without E2 as a new agent for modulation of vascular
injury and atherogenesis for the prevention of cardiovascular diseases
in post-menopausal women |
