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Release: Oct. 29, 2001
UI study investigates how estrogen protects against cardiovascular disease
IOWA CITY, Iowa -- Restoring estrogen levels to premenopausal levels in cells
taken from postmenopausal rats inhibits processes that cause cardiovascular
diseases, according to a University of Iowa study. The researchers hope that
their findings will point the way to more specific treatments for these diseases
in postmenopausal women.
The findings appear as a highlighted topic in the November issue of the Journal
of Applied Physiology. The UI researchers also contributed to a commentary
accompanying the article.
Studies have shown that estrogen protects women against cardiovascular system
diseases such as atherosclerosis. Estrogen is a hormone that acts in the cell
through its receptor protein. After menopause, less estrogen is produced and
the amount of the receptor protein is reduced. As a result, cardiovascular
disease becomes a major cause of death and illness for postmenopausal women.
Hormone replacement therapy decreases the age-associated risk of cardiovascular
disease in postmenopausal women by up to 50 percent. However, the mechanisms
by which estrogen provides protection are not clear. Also, although estrogen
has a beneficial effect on the cardiovascular and bone systems of postmenopausal
women, it may be linked to an increased risk of breast cancer and cancer of
the uterus (endometrial cancer).
"Our research is aimed at discovering how estrogen can provide its protective
effects," said Ram V. Sharma, Ph.D., UI research scientist in anatomy
and cell biology, and lead author of the study. "If we know how the estrogen
effect is regulated in the cardiovascular system, then we can develop better,
more specific estrogenic drugs to treat cardiovascular disease, which will
not have an effect in breast or endometrial tissue."
To investigate the effects of estrogen on the vascular system in pre- and
postmenopausal females, the UI team used blood vessel cells from female rats
typically used to study aging processes.
"We used two age groups that would be considered to represent young
adult rats and old adult rats," said Ramesh C. Bhalla, Ph.D., UI professor
of anatomy and cell biology and principal investigator of the study. "The
young adults, like a young women, have normal estrogen cycles. But the older
rats have stopped estrogen cycling, which makes them a good model for postmenopausal
The researchers found that the vascular cells from old females multiply faster
than those from young females. This signals a problem for postmenopausal females
because this proliferation is a
hallmark of many vascular diseases, including atherosclerosis, where cell
plaques build up inside blood vessels, causing blockages. Additionally, surgery
to remove such plaques causes some damage to the blood vessel, which the body
repairs by inducing cell proliferation. In older females this response is
too great and, rather than healing the blood vessel, over-proliferation causes
new blockages. This problem is known as restenosis.
The researchers investigated whether restoring the estrogen cycle would inhibit
this proliferation. They found that adding normal levels of estrogen to the
rat cells reduces proliferation in both old and young cells and the effect
was significantly greater in the cells from postmenopausal rats. The scientists
also used gene therapy to introduce an estrogen receptor protein into the
cells. Adding the receptor protein back into the cells from older animals
increased the beneficial, anti-proliferative effects of estrogen treatment.
These findings suggest that estrogen's protective effect against cardiovascular
diseases stems from the hormone's ability to inhibit proliferation of cells
in the vascular system. The findings raise the possibility of using gene therapy
as a localized treatment for these diseases in postmenopausal women.
"You can envisage using a localized gene therapy with the estrogen receptor
or simply giving estrogen-type compounds to damp down the over-proliferation
effect and suppress the adverse effect of restenosis," Sharma said.
Building on their findings, the UI team took the next step to try and understand
which underlying cellular processes are regulated by the estrogen cycle.
It is commonly believed that inflammatory processes are involved in vascular
system diseases such as atherosclerosis and restenosis. A protein called NF
kappa B, which helps to regulate genes that produce inflammation, is thought
to help cause these diseases.
The researchers found that activation of NF kappa B is increased in blood
vessel cells from postmenopausal rats compared to cells from young females.
The experiments also proved that estrogen inhibits this activation and using
gene therapy to restore the estrogen receptor protein to the "old"
cells boosted this inhibition.
"Now we have a system where we use gene therapy to control damaging
cell proliferation," Bhalla said. "We have also gone one step further
and shown that the gene therapy works by inhibiting the action of NF kappa
NF kappa B and the estrogen system appear to be two sides of a delicate balance.
NF kappa B induces inflammation and proliferation, while estrogen mediates
genes that reduce these cellular processes.
"We need both these proteins but it is important that they be in balance,"
Sharma said, he likened menopause to taking the brakes off the NF kappa B
"Now we have shown that you can provide the brake by adding estrogen
or estrogen receptor to compete down the harmful effects of NF- kappa B."
The UI study was funded by grants from the National Institutes of Health
and the American Heart Association. In addition to Bhalla and Sharma, Milind
V. Gurjar, a graduate student in Bhalla's lab, was also involved in the study.
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