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."