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Hypertension News
Article Date: 17 Sep 2006 - 15:00pm (PDT)
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A gene mutation of a key enzyme that regulates
smooth muscle contraction and blood pressure in rats
has been identified by researchers at the University
of Illinois at Chicago. The finding, the first
genetic link to muscle contraction and high blood
pressure, may lead to improved treatments for
hypertension.
The study appears in the September issue of
Molecular Biology of the Cell.
When myosin, a protein that is abundant in muscle
and is necessary for muscle contraction, is
activated, smooth muscle cells in blood vessel walls
contract and raise blood pressure. The cells also
proliferate, thickening the walls and narrowing the
channel, further increasing blood pressure.
Together, this results in hypertension, according to
Dr. Primal de Lanerolle, professor of physiology and
biophysics and senior author of the study. The
current crop of drugs used to treat hypertension
mainly targets contraction of the smooth muscle
cells. They do not affect the proliferation of the
cells, and the thickening of the walls of blood
vessels is presently irreversible.
In the new study, the researchers were able to
confirm the increased levels of the activated form
of myosin in hypertensive rats, a widely used animal
model of hypertension. More importantly, they
established why myosin activation is elevated and
linked the mechanism to a gene mutation.
The researchers found there was more of a protein
called smooth muscle myosin light chain kinase,
which activates myosin, in their hypertensive rats
than in closely related rats that do not develop
hypertension. They also found that there was more of
the kinase's messenger RNA, the genetic message the
cell uses to make the kinase.
"This told us that whatever was happening to raise
levels of the kinase was happening at a genetic
level," de Lanerolle said.
Although secondary hypertension may result from
another disorder or from some medications, essential
hypertension -- the most common form of high blood
pressure -- has no known cause. Genetic,
environmental and behavioral factors, such as diet,
are believed to play a role, but no gene mutations
have been identified in proteins that regulate
smooth muscle contraction in essential hypertension.
Dr. Yoo-Jeong Han, research associate in physiology
and biophysics and lead author of the study,
determined the DNA sequence of the stretch of the
kinase gene that controls how often it is copied,
and thus controls the level of kinase in the cell.
She found a mutation in the hypertensive animals --
an insertion of a small extra piece of DNA.
The insertion changes the shape of the gene
slightly, Han said, making it easier for a
transcription factor (another protein that is
essentially an on/off switch for genes) to bind and
turn on the kinase gene.
"The result is more copies of the gene, more of the
kinase in the cell, and, ultimately, more
contraction and proliferation of smooth muscle
cells," she said.
The transcription factor that binds the mutated gene
more easily is part of a cell signalling pathway.
This pathway is activated by a protein called Ras,
and mutations in Ras have been previously implicated
in numerous human cancers.
"When we blocked Ras signalling in the hypertensive
rats, we were able to block the proliferation of the
smooth muscle cells in the vessel walls and the
development of hypertension," said de Lanerolle.
The next question, according to de Lanerolle, is
whether a similar mechanism operates in humans to
cause essential hypertension.
"If we find a similar mutation in the equivalent
human gene, it will make it easier to identify
people at risk for developing hypertension," de
Lanerolle said. "People with a genetic
predisposition to hypertension would be able to
lower their risk through behavioral change or,
someday, perhaps, drug therapy."
###
We-Yang Hu, Olga Chernaya, Nenad Antic, Lianzhi Gu
and Mariann Piano of UIC and Mahesh Gupta of the
University of Chicago also collaborated on the
study, which was supported in part by grants from
the National Institutes of Health. Yoo-Jeong Han and
Wen-Yang Hu are supported by the American Heart
Association.
Contact: Jeanne Galatzer-Levy
University of Illinois at Chicago
