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UCSD RESEARCHERS FIND KEY MOLECULE THAT PROTECTS AGAINST HEART FAILURE
Researchers at University of California, San Diego (UCSD) School of Medicine have identified a key link in a chain of events that protect the heart from cell death, which leads to heart failure. Heart failure is one of the principal causes of death and disability in the United States and in many developed nations.
The findings, described in the April 16 issue of the journal Cell, could lead the way to targeted new drug therapies for heart attacks, hypertension and the heart-damaging effects of some cancer treatments.
In the paper, Kenneth R. Chien, M.D., Ph.D., professor of medicine at the UCSD School of Medicine, and colleagues from UCSD and the University of Cologne, Germany, clearly demonstrate in mice that a cell-surface receptor called gp130 triggers a molecular sequence of events that protect the heart from cell death.
During periods of stress to the heart muscle such as high blood pressure, injury or infection, two competing pathways are activated -- one that protects the heart and one that causes cell death. The protective pathway is activated when cytokine growth factors (chemical messengers) such as cardiotrophin-1 are released. Cardiotrophin-1 seeks out and binds to the gp130 receptor in a lock-and-key fashion. That union activates a gene that blocks the cell-death pathway.
"Now that we know unequivocally that gp130 is the target, it may be possible to develop a biological, or natural, therapy based on cardiotrophin-1 or other growth factors in that family," Chien said. "We may be able to enhance the heart cell's natural protective mechanism."
Chien believes such a therapy would be most useful in short, potent stress periods, like a heart attack, and could also be used to prevent heart damage that can result from chemotherapy for breast cancer.
"We are cautiously hopeful that this will lead to a new class of drugs for preventing the onset of heart failure that arises from many different causes," he said.
The UCSD team developed a special laboratory animal called a "designer knockout mouse" that lacked the gp130 receptor only in the heart and left it present in all other tissues. It was one of the first examples of a new generation of knockout mice in which a gene has been specifically mutated in a specific tissue.
The mice lacking the gp130 receptor had normal heart structure and function, but during stress similar to severe hypertension they rapidly developed enlarged hearts and massive destruction of heart muscle cells.
"We've now been able to show in a living organism that the gp130 receptor and the protective pathway it launches are critical to protecting the heart against heart failure," said Chien.
One of the next steps, he says, is to see whether cardiotrophin-1 or its related growth factors, when given as a drug therapy, can protect the heart from damage without enlarging it.
Chien explained that in order to protect the heart and keep it pumping during high blood pressure, injury or infection, the protective pathway allows the heart to adapt by increasing the size of individual muscle cells, which leads to heart enlargement, called hypertrophy.
Although the enlarged heart allows the person to survive the initial stress, the process can also cause the heart to become weaker, the chambers to thicken and stiffen, and pumping to become less efficient. Hypertrophy can eventually lead to decrease in heart function, heart failure and premature death.
"Since the gp130 pathway leads to less cardiac injury, our hope is that there will be less heart hypertrophy in the long run, as well," Chien said.
Chien is a member of UCSD's Center for Molecular Genetics and is co-director of the UCSD Cardiovascular Center, a center that brings together leading experts in basic science and clinical care to develop new preventive, diagnostic and therapeutic techniques for heart disease. A special focus of the center involves new methods for the early recognition and treatment of heart failure. He is also director of the UCSD/Salk Program in Molecular Medicine, which is a training program for physician-scientists, sponsored by the National Institutes of Health.
Other contributors to the Cell paper include Hisao Hirota, Ju Chen, Yusu Gu, and John Ross Jr. in the UCSD Department of Medicine; and Ulrich A.K. Betz, Klaus Rajewsky and Werner Muller at the University of Cologne, Germany.
This research was supported by the National Institutes of Health.
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NOTE: Copies of the paper, titled "Loss of a gp130 Cardiac Muscle Cell Survival Pathway Is a Critical Event in the Onset of Heart Failure During Biomechanical Stress," may be obtained from Cell at (617) 661-7057, Ext. 129 (phone), or (617) 661-7061 (FAX).
4/09/99
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