New Model Shows Gender Differences in High Blood Pressure, Jefferson Scientists Find


New Model Shows Gender Differences in High Blood Pressure,
Jefferson Scientists Find
October 06, 2005
Researchers at Jefferson Medical College have implicated a
protein called GRK5 as having an
important role behind essential hypertension, which affects more
than 65 million Americans.


When Andrea Eckhart, Ph.D., associate professor of medicine at
Jefferson Medical College of Thomas Jefferson University in
Philadelphia, and her co-workers turned up the
volume on GRK5, overexpressing a
mouse gene that makes the
protein, the researchers saw
extreme rises in blood pressure even when the animals were
resting.
Not only that, they found that high blood pressure segregated
with gender.

That is, female mice with an overexpressed GRK5-making
gene had a lesser spike in blood pressure than males, which Dr.
Eckhart says, has intriguing implications.
"This difference suggests it could be a great model for human
hypertension, especially for premenopausal women," says Dr.
Eckhart, who is director of the Eugene Feiner Laboratory in the
Center for Translational Medicine in the Department of Medicine at
Jefferson Medical College.

"Is the difference due to a protective
effect of estrogen, or because males with testosterone make it
worse? We're now looking at the effects of these androgens in
conferring differences."
Dr. Eckhart thinks it could be a "powerful hypertensive model to
look at different new hypertensive therapies that different drug
companies come up with to look at the effects of estrogen."
To Dr.

Eckhart and her group, which reported their results
August 23, 2005 in Circulation, a journal of the American Heart
Association, the finding is another step in the laboratory's goal
of uncovering the molecular roots of hypertension. More than 90
percent of
cases can't be pinned to a
particular molecular cause.
GRK5, short for G-coupled protein receptor kinase, was known to
rise in animal models with high blood pressure. According to Dr.


Eckhart, this kinase acts as a switch that essentially turns off
receptors. Such receptors bind catecholamines, which are
sympathetic system neurotransmitters like epinephrine and
norepineprhine. They also bind peptide hormones such as
angiotensin, which is implicated in high blood pressure.
Dr.

Eckhart and her co-workers don't think that GRK5 is
necessarily the sole cause of hypertension. But because it is
correlated with some types, they wanted to look at the molecular
mechanisms and try to get a better idea of its role. They created
mice that overexpressed GRK5 in the vascular smooth muscle, hoping
to "begin seeing what receptors and signaling pathways might be
involved in hypertension with elevated GRK5 levels." What they
found surprised them.


"There are not too many molecules shown in mice to raise basal
blood pressure straight up," she says. "The effect is quite
profound. There are a lot of checks and balances that keep the
pressure down. We were surprised there was such an increase at
resting.

We might have thought this would happen if we stressed the
animal, but we saw it at baseline. Obviously it is affecting
receptors important in the resting state."
When they looked more closely, they found that increases in
blood pressure differed according to sex.
"Ultimately, we'd like to see if GRK5 is a biomarker, a
predictor for a multifactorial disease like high blood pressure,"
she says.

"Developing a good therapeutic profile for such patients
might helps us prescribe the correct drugs more quickly. We hope
the work might lead to better, more specific ways to treat high
blood pressure than currently used diuretics and specific receptor
blockers."
She notes that even though these mice have hypertension, their
blood vessels are not enlarged, which is typical of progressive
heart failure and kidney disease and are associated with high blood
pressure. "These mice didn't have these associated cardiovascular
risks," she says.

"Maybe the GRK5 is somehow protective of other
organs, despite its role in causing hypertension.
Dr. Eckhart's group, in collaboration with Bonita Falkner, M.D.

,
professor of medicine at Jefferson Medical College and Kumar
Sharma, M.D., director of the Center for Diabetic Kidney Disease at
Thomas Jefferson University and professor of medicine at Jefferson
Medical College, currently is studying children with hypertension
to examine white blood cell levels of GRK5.
Thomas Jefferson University Hospital

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