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New ’molecular switch’ protein protects the heart from major cardiovascular damage

23.01.2006


U-M researchers report dramatic benefits from a single amino acid substitution in troponin I cardiac muscle protein



It’s just one little amino acid, but it makes all the difference in protecting the heart from the harmful effects of heart attack and cardiac failure. Researchers from the University of Michigan Medical School suggest this amino acid, called histidine, could be the key to a new therapy for cardiovascular disease.

In a study to be published Jan. 22 in Nature Medicine as an advance online publication, U-M scientists describe how they created a modified form of a heart muscle protein called troponin I and how it improved cardiac function in mice and in damaged human heart cells. The secret was using genetic engineering technology to replace one amino acid called alanine, found in the adult form of troponin I, with a histidine from the fetal form of the same protein.


"The most important finding of our study was that this modified troponin I protein dramatically improved heart function under a variety of conditions associated with cardiovascular damage and heart failure," says Sharlene Day, M.D., an assistant professor of internal medicine in U-M’s Cardiovascular Center and co-first author of the Nature Medicine paper.

"This study provides the first evidence that a single histidine substitution in troponin I can improve short and long-term cardiac function in laboratory mice with heart failure," says Joseph M. Metzger, Ph.D. – a professor of molecular and integrative physiology and of internal medicine in the U-M Medical School. "The fact that we also were able to rescue the functionality of damaged human heart cells is a significant advance."

Metzger believes U-M’s modified troponin I protein could become the basis of a new gene therapy or cell-based therapy for heart disease and heart failure. Progressive heart failure affects 4.8 million Americans. Despite current medical and surgical therapies, mortality remains high.

Troponin I is an important cardiac muscle regulatory protein that controls the calcium sensitivity of heart muscle cells. The ability to respond to calcium is important, because it’s what causes the heart to contract efficiently and pump blood through the body. When blood flow to the heart is compromised, such as during a heart attack, acid accumulates in cardiac cells – a condition called acidosis. This causes cells to become less responsive to calcium, which can lead ultimately to heart damage and cardiac failure.

During embryonic development, the fetal form of troponin I is present in the fetal heart, which makes it more resistant than the adult heart to the harmful effects of acidosis and low oxygen that can occur during pregnancy or delivery. This means that fetal hearts largely retain their ability to respond to calcium under adverse conditions.

"Shortly before or after birth, the gene for fetal troponin I is turned off and the adult gene is turned on," says Margaret Westfall, Ph.D., an assistant professor of surgery in U-M’s Cardiovascular Center and co-first author of the Nature Medicine paper. "Although the adult form of troponin I is more susceptible to the harmful effects of acidosis, it has other important properties that enable the adult heart to respond to hormones during exercise and periods of stress."

In essence, U-M researchers created a "genetic hybrid" of troponin I to combine the advantages of the fetal and adult form of the protein. According to U-M scientists, the modified protein helps the heart respond to a harsh intracellular environment by boosting its performance during periods of stress.

"By making this single histidine substitution in the adult form of troponin I, we retain hormonal responsiveness and provide protection from acidosis in the same molecule," Day says. "Several heart conditions can cause acidosis in the adult heart, most notably when the heart is deprived of oxygen and nutrients due to compromised blood flow – a condition known as ischemia. When ischemia is prolonged, it can cause permanent heart muscle damage in the form of a heart attack."

"The transition from the fetal to adult form of troponin I worked well throughout most of human evolution, but the problem now is our Western lifestyle and diet, which can damage the heart," Metzger explains. "Plus, people live into their 80s or 90s, so there’s more time for ischemic heart disease and heart failure to develop."

In a series of experiments, U-M researchers studied the effects of the histidine substitution in troponin I on 1) transgenic mice with the modified form of the protein and normal littermates without the modified protein, 2) hearts removed from both types of research mice, and 3) heart cells called myocytes, which were isolated from rats and from severely damaged human hearts of U-M Health System patients who received heart transplants.

In experiments with isolated myocytes, Westfall used a virus to deliver the modified troponin I gene. When she analyzed cells for expression of troponin I with the histidine substitution, Westfall discovered that "you don’t need 100 percent gene replacement to see a biological effect in individual myofilaments. We see favorable effects at 20 percent to 50 percent replacement," she says.

To create the damaging conditions that develop in heart muscle cells when clogged blood vessels or a heart attack interrupt the heart’s oxygen supply, Day tied off one of the main arteries carrying blood to the hearts of mice in the study. Day found that hearts from transgenic mice performed far better after the procedure than hearts from mice without modified troponin I.

The U-M research team also found that hearts from transgenic mice contracted more efficiently and used less energy to perform more work than hearts from non-transgenic littermates.

The U-M research team is studying the effects of the genetically engineered troponin I protein in other research animals and exploring mechanisms responsible for its heart-protective effect. They believe the modified troponin I protein senses changes within cardiac muscle cells and responds by improving the cells’ ability to contract efficiently in response to stress.

The University of Michigan has filed a patent application on the genetically engineered troponin I protein and its method for regulating cardiac performance. U-M is looking for a commercialization partner to market the technology.

Sally Pobojewski | EurekAlert!
Further information:
http://www.umich.edu

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