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University of Cincinnati Academic Health Center
Publish Date: 03/13/07
Media Contact: AHC Public Relations, (513) 558-4553
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Protein Fault Provides Clue to Heart Failure

An international research team studying causes of heart failure in genetically engineered mice and human tissue have found a fault in the “calcium channel”—a cellular mechanism that is essential for maintaining heart beat—that could provide a key to understanding how human hearts fail, and what to do about it.


Study participant Arnold Schwartz, PhD, DSci, director of the Institute of Molecular Pharmacology and Biophysics at the University of Cincinnati (UC), says the findings provide a new target for genetic treatment of human heart failure, and raise the possibility of a new diagnostic approach as well.


The study, published in the March 14, 2007, edition on the online journal PLoS ONE, was an international collaboration also involving Roger Hullin, MD, of the Swiss Heart Center, Bern; Stefan Herzig, MD, PhD, and Jan Matthes, MD, of the University of Cologne, Germany; and Ilona Bodi, PhD, University of Cincinnati.


It has long been known that calcium plays a key role in controlling heart beat. To do so it passes through a protein channel, or pore, which in turn is regulated by a group of “accessory” proteins, a major component of which is the beta-2a regulatory protein.


What this study found, says Schwartz, who has been studying calcium channels for 25 years, is that in many types of terminal human heart failure this beta-2a protein is increased or “over-expressed,” and that the electrical activity in the heart’s cells show a distinct pattern of “single-channel” activity, an indicator that the influx of calcium into the heart has also increased.


The researchers in Switzerland, Germany and the United States studied a mouse model with an over-expressed pore that was developed in Schwartz’s laboratory. As a consequence of the over-expression, the animal’s heart received a sustained increase of calcium, Schwartz says, and slowly became overdeveloped (hypertrophied) and eventually failed. All the changes in the animal model—biochemical, physiological and pathological—resembled the human heart process.


“When the model is adapting to the increased calcium with each heartbeat, you don’t see anything wrong with the heart,” Schwartz explains. “But we found that the beta-2a protein compensates for the protein increase by becoming under-expressed, while single-channel activity remains very normal looking.”


As the animal ages, Schwartz says, the heart begins to fail, beta-2a increases and single-channel calcium activity looks almost identical to that in a failing human heart.


A second major component of the collaborative study was to genetically engineer a mouse model in which beta-2a in the heart was over-expressed from birth. When that mouse was mated with a young mouse in an adaptive phase, the transgenic offspring showed over-expressed beta-2a, and a single-channel pattern identical to that in the older mouse and the failing human heart.


“This is about as close as we have gotten so far to cause and effect,” says Schwartz. “We need to do much more research, but it’s possible that somehow nature provides a mechanism in which the heart is able to adapt to certain stresses by changing the amount of a particular accessory protein, in this case beta-2a, which regulates the calcium channel.


“We’re still investigating how this happens,” Schwartz says. “But if it’s so, the question then is what can be done about it therapeutically.


“The most exciting possibility is to lower beta-2a in a heart that’s beginning to fail, because if you keep beta-2a low, the heart won’t fail. This finding opens the way to new genetic approaches to heart failure.”


Funding for the research done in the United States came from two grants held by Schwartz from the National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health.





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