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http://circ.ahajournals.org/content/126/16/1993.full?sid=f0c284a1-0bfb-4bfb-aa86-081f003c9c2c [FULL]
Circulation. 2012; 126: 1993-2004 Published
online before print September 20, 2012
Rapid Estrogen Receptor Signaling Is Essential for
the Protective
Effects of Estrogen
Against Vascular Injury
Abstract
Background—Clinical trial
and epidemiological data support that the
cardiovascular effects of estrogen are complex, including a mixture of both
potentially beneficial and harmful effects. In animal models, estrogen protects females
from vascular injury and
inhibits arteriosclerosis. These effects are mediated by estrogen receptors
(ERs), which, when bound to estrogen, can bind to DNA to directly regulate
transcription. ERs can also activate several cellular kinases by inducing a rapid
nonnuclear signaling cascade.
However, the biological significance of this rapid signaling pathway has been
unclear.
Methods and Results—In
the
present study, we develop a novel transgenic mouse in which rapid signaling is
blocked by overexpression of a peptide
that prevents ERs from interacting
with the scaffold protein striatin (the
disrupting peptide mouse). Microarray
analysis of ex vivo treated mouse
aortas demonstrates that rapid ER
signaling plays an important role in estrogen-mediated
gene regulatory responses. Disruption
of
ER-striatin interactions also
eliminates the ability of estrogen
to stimulate cultured endothelial cell
migration and to inhibit cultured
vascular smooth muscle cell growth. The
importance of these findings is underscored
by in vivo
experiments demonstrating loss of
estrogen-mediated
protection against vascular injury in the
disrupting peptide mouse after carotid
artery wire injury.
Conclusions—Taken together, these
results support the concept that rapid,
nonnuclear ER signaling contributes
to the transcriptional regulatory
functions of ER and is essential for many of the
vaso-protective effects of
estrogen [vaso vasorum]. These findings also identify the rapid ER signaling pathway as a
potential target for the development of
novel therapeutic
agents. [Vaso vasorum are blood vessel that supply oxygen and nutrients to the
cell in the artery wall. Damaged
vaso
vasorum promote infection therein and arteriosclerosis.
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http://circ.ahajournals.org/content/95/6/1505.short Estradiol
as a Survival Factor; 1997; 95: 1505-1514
Estrogen-Receptor–Mediated
Inhibition of Human
Endothelial Cell Apoptosis
Abstract: Background A series of studies was performed to examine the
ability of estradiol (E2) to protect endothelial cells from
apoptosis.
Methods and Results Light and transmission
electron microscopy
demonstrated typical features of apoptosis in human umbilical vein endothelial
cells (HUVEC) exposed to tumor necrosis factor-α (TNF-α). Northern and Western
blot analyses revealed induction of message and protein for the interleukin-1β
converting enzyme (ICE), which has been shown to mediate apoptosis induced by
TNF-α. Immunofluorescent staining of HUVEC colocalized ICE expression to
apoptotic HUVEC. Direct cell counting demonstrated a significant decrease in total
endothelial cell number after 24 hours of TNF-α exposure and a dose-dependent
reversal of the effect of TNF-α with E2 treatment. This protective
effect was abrogated by an estrogen-receptor antagonist. Fluorescence-activated
cell sorting analysis revealed 39.3% apoptosis after 24 hours of TNF-α
exposure. Treatment with E2
resulted in a 50% decrease in apoptosis. Similarly, viability assays
revealed 35±4% cell death after TNF-α exposure. Simultaneous treatment with E2
resulted in a dose-dependent reduction of cell death to a minimum of 18±2%. The protective effect of E2 was
nullified by a specific estrogen-receptor antagonist.
Conclusions E2 treatment resulted in a dose-dependent,
receptor-mediated inhibition of TNF-α–induced endothelial cell apoptosis. These
studies indicate that E2 may also serve a maintenance function in
preventing endothelial cell death after noxious stimuli and suggest that the
ICE pathway may mediate cytokine-induced apoptosis in endothelial cells.
Preservation of endothelial integrity represents another mechanism that may
account for the atheroprotective effect of estrogen.
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I believe that the
fall in
testosterone level from the youth level explains the middle-age risk for
men. This decline has accelerated
for
men since 1910 in that there is nearly a 40% decline in testosterone when
compared to that of a century ago—probably a result of dietary estrogen and
testosterone mimics. For article
on
population level decline: http://jcem.endojournals.org/content/92/1/196.full
http://circ.ahajournals.org/content/103/10/1382.full?sid=ebc77905-be20-4f61-90c6-248cec066b77 Circulation. 2001; 103:
1382-1385
Effect of Testosterone on
Plaque Development and Androgen Receptor Expression in the
Arterial Vessel Wall
Abstract
Background—Recent studies have
suggested that testosterone has a protective
effect in the arterial vascular system.
However, little is known about the molecular aspects of the
mechanism(s) involved in these
processes. The aim of the
present study was to investigate the
effect of testosterone on
neointimal plaque development and on the
expression of
the vascular androgen receptor.
Methods and Results—Neointimal
plaque formation was induced by endothelial
denudation in the
aortas of male New Zealand White
rabbits. Aortic ring segments were cultured for 21 days after endothelial denudation. Testosterone was applied to the culture medium in different doses.
Compared with the non–hormone-treated
control group, a significant inhibition
of
neointimal plaque development (expressed as the
intima/media ratio) was found at testosterone
concentrations of
10 ng/mL (P=0.037) and 100 ng/mL (P=0.012; intima/media
ratios: median of controls, 0.25;
median of 10 ng/mL testosterone group,
0.15; median of 100 ng/mL testosterone
group, 0.16). Associated with this
inhibitory effect on plaque size was a
50% increase of the amount of androgen receptor mRNA in the arterial segments
treated with testosterone.
Conclusion—The
beneficial effects of testosterone on
post injury plaque development underlines, at least in males, the important role of androgens
in the vascular system. As our data suggest, the
vascular androgen receptor is probably involved in these processes. Further studies are required to characterize the androgen receptor–dependent pathways in the vascular system.
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Numerous
studies prove the protective effects of HRT—unfortunately they include all
forms of estrogen and various progestins.
Given the rareness of MI in premenopausal women compared to men of
similar age and the increase in events following menopause, this is strong
evidence for the superiority of natural
HRT. Though I couldn’t
find NHRT trials, because progesterone
is
not orally active and was not available as a pill until about 2005, when it was
micronized in oil, the Danish study
(below) using triphasic estradiol and
norethisterone acetate is the closest I could find. The frequency of major events, death, cancer,
and
heart failure, was reduced over 100% from 33 in the placebo group to 16 for
those on HRT.
HRT was used
for 11 years, and the women were tracked for 16 years. They used the Danish national hospital
registry to track outcomes “with an almost 100% completeness of recording and a
high precision of diagnoses”. “Deaths due to
cardiovascular causes occurred in 18 women in the control group and five in the
treated group.”
Effect of hormone replacement therapy on
cardiovascular events in recently postmenopausal women: randomised trial
Cite this as: BMJ 2012;345:e6409 http://www.bmj.com/content/345/bmj.e6409?etoc
Participants 1006 healthy women aged 45-58 who
were recently postmenopausal or had perimenopausal symptoms in combination with
recorded postmenopausal serum follicle stimulating hormone values. 502 women
were randomly allocated to receive hormone replacement therapy and 504 to
receive no treatment (control). Women who had undergone hysterectomy were
included if they were aged 45-52 and had recorded values for postmenopausal
serum follicle stimulating hormone.
Interventions In the treatment
group, women with an intact uterus were treated with triphasic
estradiol and norethisterone acetate and women who had
undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped
after about 11 years owing to adverse reports from other trials, but
participants were followed for death,
cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses
were carried out on women who took more than 80% of the prescribed treatment
for five years.
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Extract
by JK from the highly
regarded Harvard Nurse’s Health Study. This
population study includes all forms of HRT including Prempro, the worse.
Over 70,000 nurses participated in the
study.
http://test.europepmc.org/abstract/MED/1870648
NEJM 1991, 325(11):756-762
Postmenopausal estrogen
therapy & cardiovascular disease. Ten-year follow-up from the nurses' health
study.
RESULTS: After adjustment for age and other
risk factors, the overall
relative risk of major coronary disease in women currently
taking estrogen was 0.56
(95 percent confidence interval, 0.40 to 0.80); the risk was significantly
reduced among women with either natural or surgical menopause. We observed no
effect of the duration of estrogen use independent
of age.
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1997;
96: 2468-2482
This article besides the major CHD benefit of
HRT, showed that it was well documented the adverse effects of MPA used in
Prempro for the HRT in the landmark NIH’s Women’s Health Initiative (WHI).
Cardiovascular Disease in Women
A Statement for Healthcare Professionals From
the American Heart
Association
http://circ.ahajournals.org/content/96/7/2468.full
Based on
meta-analyses of studies, most from the United States,184
185
postmenopausal estrogen is associated with a 35% to 50% reduced risk of CHD. On
the basis of a calculation of overall risks and benefits, a healthy woman at no
particular increased risk for heart disease, cancer, or osteoporosis would gain
on average 1 additional year of life.185 As
reviewed elsewhere,188 189 there are
multiple mechanisms whereby estrogen might protect against CHD, including
favorable changes in lipids, lipoproteins, fibrinogen and PAI-1, vasomotor
effects, and antioxidant effects. In a
recent study,192 232 women
who had used estrogen since menopause for an average duration of 17 years had
nearly 50% lower mortality from all causes than age-matched nonusers (95%
CI=0.38-0.76); reduced mortality was largely due to less fatal CVD. A report
from the Nurses’ Health Study 187 showed a
reduced risk of nearly every disease except breast cancer. A recent Markov
analysis193 postulated
a 3-year increase in life expectancy associated with use of postmenopausal
estrogen…. These studies had relatively
few events, however, and several new lines of evidence suggest that
medroxyprogesterone acetate may mask or at least partially reverse estrogen-induced
benefits. Other studies show that
medroxyprogesterone
acetate can have a particularly deleterious effect on estrogen-induced
improvements in vascular reactivity and arteriosclerosis. For example, recent
studies in nonhuman
primates showed that conjugated equine estrogen alone—but not estrogen combined
with medroxyprogesterone acetate—improved vascular reactivity of coronary
arteries198 and
prevented the progression of coronary artery arteriosclerosis.199
