Identifying Molecular Targets In Heart Ischemia Could Lead To Two Therapies

September 12, 1997

Potential Therapy To Protect Heart Cells from Loss of Blood Flow:
Ischemic heart disease, which results when heart cells don't get enough oxygen, accounts for many of one-and-a-half million heart attacks Americans suffer annually. Working with cardiac muscle cells, or myocytes, from chick embryos, Bruce T. Liang, MD, an associate professor of medicine at the University of Pennsylvania Medical Center, is beginning to identify molecular targets that could lead to therapies for this type of heart condition. Liang's group found a new receptor for the nucleic acid derivative adenosine on the surface of myocytes. Cardiac myocytes release adenosine under such stressful conditions as blockage of the coronary artery. In this study, Liang exposed cardiac myocytes to simulated ischemia, causing them to release a large amount of adenosine. This molecule binds to receptors on the surface of the myocyte, activating a number of steps that cause myocytes to become more resistant to the deleterious effects of ischemia. "In essence, the affected cells shut down as a result of adenosine activation," says Liang. "If we can somehow enhance activation of the adenosine receptors, we could potentially reduce the severity of a heart attack. When we do this in cardiac cells, damage due to ischemia is much reduced." The clinical implication, he says, is that adenosine mimics could be given as drugs to alter the effect of a heart attack. Potential drugs would attach in a lock-and-key fashion to the adenosine receptor, triggering the molecular events that cause the cells to shut down. These findings were published in the July issue of the American Journal of Physiology.

Pre-conditioning Therapy Could Help Reduce Operation-Associated Heart Attacks:
In a companion paper to his adenosine receptor article--published in the August issue of the American Journal of Physiology--Bruce T. Liang, MD, an associate professor of medicine, describes another cardiac protective phenomenon called pre-conditioning . Here, the heart is protected from anticipated ischemic damage. During surgery people with coronary artery disease often develop heart attacks due to ischemia. "If the heart is exposed to a short period of ischemia, then it might become more resistant to the impact of a prolonged subsequent ischemic attack," explains Liang. "Using chick myocytes, we have developed a cardiac-cell model for ischemic pre-conditioning to study the molecular pathways that underlie it. If we understand the mechanism, then we should be able to formulate protective therapies." Ischemic pre-conditioning is also triggered by adenosine, which activates an enzyme called protein kinase C, which induces chemical changes in cellular membrane ion channels. Ultimately, changes to this channel protect the cardiac cells from damage. Ischemic preconditioning has been demonstrated in intact hearts of many species, including humans. "If we can pre-condition the heart before surgery with a drug that acts on the ion channel, then perhaps we may lessen the chances of an attack," he says.

Note: Dr. Liang can be reached at 215-349-5674.

The University of Pennsylvania Medical Center's sponsored research ranks fifth 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 1996, the medical center received $149 million. In addition, for the second consecutive year, the institution posted the highest growth rate in research activity--9.1 percent--of the top-ten U.S. academic medical centers during the same period. 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 home page (http://www.med.upenn.edu) and EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science.

University of Pennsylvania School of Medicine

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