|
June 8, 1998
Newly Recognized Cell-Surface
Receptor Protects Heart Tissue Against Damage
Scientists at the University of
Pennsylvania Medical Center and the National
Institutes of Health (NIH) have identified a new
molecular target that could lead to novel and
improved therapies for ischemic cardiovascular
disease. This disease, which occurs when heart
cells don't get enough oxygen, accounts for nearly
90 percent of the 1.5 million heart attacks
Americans suffer annually.
The research team found that receptors for
adenosine -- a nucleic-acid derivative -- found on
the surface of ventricle cells exert a powerful,
sustained protection against injury during exposure
to ischemia. "Consequently, adenosine mimics could
be given as drugs to alter the effect of a heart
attack," suggests cardiac biologist Bruce T. Liang,
M.D., associate professor of medicine at Penn.
"Potential drugs would attach in a lock-and-key
fashion to the adenosine receptor, triggering
molecular events that could reduce the severity of
a heart attack."
"We have known for decades that adenosine
protects the heart when it is overstressed," says
co-author Kenneth A. Jacobson, Ph.D., chief of the
Molecular Recognition Section at the National
Institute of Diabetes and Digestive and Kidney
Diseases. "Now we have shown that a specific target
molecule on the cell -- the A3 adenosine receptor
-- protects the heart muscle lacking oxygen and
nutrients more effectively than any other. This
marriage of chemistry and biology brings us one
step closer to designing a drug to minimize damage
to heart muscle." Liang and Jacobson report their
findings in the June 9 issue of the Proceedings of
the National Academy of Sciences.
Heart cells release adenosine under such
stressful conditions as blockage of the coronary
artery. Adenosine binds to receptors on cell
surfaces, rendering the cells more resistant to the
deleterious effects of ischemia by essentially
shutting them down.
Previous studies from Penn, NIH, and other labs
have suggested that many types of adenosine
receptors in an array of species, including humans,
exert a protective effect on the heart, but never
to this degree of fine-tuning. This study, which
used cultured cells from chicks, teases apart the
differing effects of two receptor subtypes -- A1
and A3 -- showing that activation of A3 receptors
elicits sustained protection whereas activation of
A1 receptors triggers a short-lived effect. "We
showed that the A3 receptor is the dominant
cardioprotective receptor, and therefore should be
the one for drug targets," says Liang.
The study also showed a second difference
between the two receptors. A pre-conditioning
therapy that could help reduce post-operative heart
attacks can be induced using A3 receptors, but not
using A1. Ironically, prior exposure of heart cells
to ischemia protects them against subsequent
damage. This pre-conditioning is again triggered by
adenosine, which ultimately causes changes to heart
cell ion channels. "If we can pre-condition the
heart before surgery with a drug that acts on ion
channels, then perhaps we may lessen the chances of
an attack," notes Liang. "During heart surgery you
want to have as much of a window of protection as
possible."
The researchers also found that the protective
properties of the A3 receptor can be conferred --
via gene transfer -- onto tissues without this type
of receptor. "We've shown that chick atrial tissue,
which doesn't contain A3 receptors, can be
protected by transferring human A3 receptors into
them," states Liang. "One could potentially broaden
this to tissue types outside the heart, as long as
the machinery exists in that tissue to link up with
the receptor."
The next steps, say the researchers, will be to
develop a drug that activates the A3 receptor and
to design pre-clinical drug safety trials.
This research was funded by the National Heart,
Lung, and Blood Institute and the American Heart
Association.
The University of Pennsylvania Medical
Center's sponsored research ranks third in the
United States, based on grant support from the
National Institutes of Health, the primary funder
of biomedical research in the nation. In federal
fiscal year 1997, the medical center received $175
million. News releases from the medical center are
available to reporters by direct e-mail, fax, or
U.S. mail, upon request. They are also posted to
the center's website (http://www.uphs.upenn.edu)
and EurekAlert! (http://www.eurekalert.org),
a resource sponsored by the American Association
for the Advancement of Science.
|
|