Double Duty: Loss of Protective Heart Failure Protein Causes High Blood Pressure
Scientists
at the Center for Translational Medicine at Thomas Jefferson University
in Philadelphia have found that a protein that appears to have
protective and perhaps healing effects for failing hearts also plays a
similar role in high blood pressure. They found lower-than-normal
levels of the protein S100A1 in cells that line blood vessel walls in
animals with high blood pressure.
When
the researchers, led by Patrick Most, M.D., assistant professor of
Medicine at Jefferson Medical College and former postdoctoral fellow
Sven Pleger, M.D., experimentally lowered the amount of S100A1 protein
in the animals’ blood vessels, they were able to dramatically increase
blood pressure. The preliminary results identified a novel and rather
unanticipated biological function of the protein and suggest that
S100A1 could be a therapeutic target for blood pressure treatment. The
team’s findings appear in the journal Circulation Research.
“S100A1
seems to be a major player in the regulation of blood pressure and
vascular function,” says Dr. Most. “The mechanisms by which this works
is by producing more nitric oxide (NO) in the endothelial cells that
line the vessel walls. A lack of NO enables hypertension.”
According
to Dr. Most, S100A1 is an alternative mechanism for increasing heart
function. It directly regulates calcium circulation, which drives the
contractions in the heart. Dr. Most’s laboratory has been working on
S100A1’s role in disease hearts for more than a decade, and together
with a group led by Walter Koch, Ph.D, director of the Center for
Translational Medicine, they have proven that loss of the protein
causes diseased hearts to fail and that the protein is a potential
target for gene therapy for heart failure.
S100A1,
part of a larger family of proteins called S100, is primarily found at
high levels in muscle, particularly the heart. Falling levels of S100A1
are critical in the loss of heart-pumping strength after a heart attack
and play an important role in the progression to heart failure. A
previous study in 1989 showed that the protein was reduced by as much
as 50 percent in patients with heart failure.
In
the current work, Dr. Most and colleague Andrea Eckhart, Ph.D.,
associate professor of Medicine at Jefferson Medical College, and their
team found in both laboratory experiments and in animal models that
blood vessels that lack S100A1 cannot relax as well as normal vessels.
“If the animal doesn’t have S100A1, it has hypertension,” he says. “The
mechanism is based more or less on the availability of nitric oxide. It
seems that S100A1 also regulates calcium cycling in the endothelial
cell, and calcium is needed in the endothelial cell to stimulate NO
production. The loss of S100A1 impairs the calcium mobilization of the
endothelial cell – that’s the link between less calcium, less NO,
hypertension and endothelial dysfunction.
“As
a result,” Dr. Most says, “S100A1 might not only be a good therapeutic
target for heart failure, but for hypertension as well.” Current
projections estimate that 29.2 percent of the adult population
worldwide – about 1.56 billion people – will have hypertension by 2025.
Hypertension has long been the most common risk factor for the
development of congestive heart failure, affecting nearly five million
Americans, many of whom have poor long-term prognoses, despite recent
therapeutic advances.
The
researchers plan to continue to investigate animal models of
hypertension, noting that the current work was only possible because of
the collaborative efforts of those in the Center for Translational
Medicine and also the Department of Physiology. If the scientists find
a lack of S100A1 in blood vessels, then they will develop treatments
using the Center’s in-house capabilities to generate viral delivery
that can be tailored to express genes in endothelial cells. “We will
test genetically engineered animals to find out whether or not
replacing S100A1 can decrease blood pressure,” he notes.
In
addition, the researchers will test a recently developed approach
employing only a small fragment of the protein with a similar
therapeutic potency. “This fragment,” Dr. Most explains, “is 10 times
smaller than the protein and allows a direct application in the
bloodstream, almost like a real drug.” The researchers hope that either
the small protein fragment itself or a synthetic analogue will enable a
novel therapeutic approach to treat both heart failure and hypertensive
patients in the near future.
Media Only Contact:
Richard Cushman
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 5/2/2008