June 9, 1998 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, MD, an 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, PhD, 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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