Karen Young Kreeger, Penn
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.
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primary funder of biomedical research in the nation. In
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