Ancient Protein Provides Clues to Heart Disease

Understanding the good and bad of a 600 million-year-old protein named "tumor necrosis factor" may lead to improved strategies for treating heart failure.

"The fact that TNF is produced in the heart and has been around so long suggests that it is there for a reason," said Douglas Mann, M.D., staff physician at the Houston Veterans Affairs Medical Center and professor of medicine at Baylor College of Medicine.

Getting at the cellular and molecular intricacies of TNF is the mission of Mann’s research efforts. In his laboratory, Mann and his colleagues study TNF’s good and bad effects.

On the good side, they proved that TNF protects myocytes, the cells in the heart that contract and enable the heart to pump. Efforts are now under way to determine how this protection occurs at a molecular level.

Understanding the harmful side of TNF may also aid the development of effective heart-failure treatments.

"Increased TNF levels can cause problems with heart contraction, heart dilation, and increased cell death," Mann said. "If we can find ways to control TNF levels, there might be a way to impact the natural history of heart failure."

Heart dilation typically involves an increase in size and thinning of the heart walls. To better understand TNF’s association with heart dilation, researchers at the Houston VA Medical Center developed two strains of mice.

"One line secretes TNF and the other line, called membrane-bound TNF, secretes TNF but can’t release it into the environment," Mann said.

"Both provide us with excellent models of different types of heart failure."

The TNF-secreting mice develop enlarged hearts with thin walls – a characteristic of systolic heart failure, where the heart does not contract well. The membrane-bound TNF mice have hearts with thick, stiff walls that do not relax well – a characteristic of diastolic heart failure.

Both strains of mice provide an opportunity to better understand the processes related to heart failure.

In collaboration with Blase Carabello, M.D., chief of medicine at the Houston VA Medical Center, the team is looking at the heart mechanics of the two different mouse lines. In addition, gene array analysis allows the researchers to study the different genes expressed in these two types of heart failure.

"We also can test novel drugs on these mice," Mann said. "Testing new compounds in mice will one day lead to more effective drugs for humans."

Heart failure is a growing epidemic in the United States with 450,000 new cases a year. While 5 million Americans are affected by the disease today, that number is expected to double in the next 10 years.

"Although we have effective medications, these medications prolong life but don’t cure the disease." Mann said. "Clearly, there is room for improvement in existing strategies to treat heart failure."

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©2006 Texas Medical Center

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