Inhibiting Key Enzyme Blocks Heart Muscle Cell Death

Exciting findings reported in the May 2 issue of Cell ratchet up interest in an enzyme known as CaM kinase as a potential target for therapy in the treatment of heart disease.

Mark Anderson, M.D., Ph.D., director of the Division of Cardiovascular Medicine at the University of Iowa (UI) and senior author of the paper published in Cell, says he and his colleagues found that CaM kinase is necessary for some of the disease-causing failures of angiotension II stimulation.

“Mainly, oxidized CaM kinase causes heart muscle cell death,” says Anderson, a cardiac electrophysiologist, whose research focuses on cellular signaling and the molecular mechanisms that cause heart failure and sudden cardiac death. “Inhibiting this enzyme could block that result.”

Specifically, angiotension II is a powerful protein that causes arteries and veins to narrow, increasing blood pressure and putting a strain on the heart. According to Anderson, this protein is elevated in patients with heart failure. This protein also increases the oxidation of CaM kinase, sustaining the activity that has proven harmful to hearts.

“It turns out that the oxidation pathway for CaM kinase activation is exactly what is turned on by angiotension II.”

CaM kinase is one of perhaps a thousand other enzymes that function in some life-sustaining process. This enzyme, in fact, is critical to many fundamental physiological processes — including heartbeat and thought. When it is functioning properly, all is well. When it is excessively activated, however, it spells trouble.

Even since his days at Stanford, when he was a cardiology fellow, Anderson had a hunch that CaM kinase played a key role in heart disease. He eventually learned that the enzyme controlled the electrical pathway that causes arrhythmias — the abnormal heart rhythms that can threaten one’s life. The enzyme also switches “on” those genes that lead to mechanical dysfunction and heart failure.

After years of studies, most recently with Jeffrey Erickson, Ph.D., an UI fellow, and other researchers at UI and Vanderbilt University in Nashville, Tenn., Anderson unraveled the molecular mechanism of CaM kinase, integral to activation.

In the Cell paper, for example, he explained that you have to sort of “pull back a safety switch” to turn on excessive activation of CaM kinase. The thing that pulls back the safety is when calcium rises in the cell and piggybacks with another protein called calmodulin.

“When calcium calmodulin binds to CaM kinase, it’s cocked open and becomes active,” Anderson says. “It stays open and active by oxidizing a nearby pair of methionine amino acids in a little region that opens up when the safety comes off.”

Importantly, Anderson learned that CAM kinase oxidation — so harmful to hearts — can be reversed by another enzyme called methionine sulfoxide reductase A (MsrA). By returning CaM kinase to its inactive state, Anderson was able to block angiotension-induced cell death.

“MsrA had never been studied in the heart before,” Anderson explains. “Previously, it was identified by scientists studying longevity in model organisms like fruit flies. They found that if you didn’t have enough MsrA, you don’t live as long, which was very intriguing to us.”

"I am a physician-scientist, so my goal is to identify an unmet clinical need and to find a new treatment that will allow people to do better and live longer. In this case, the clinical need is that about half of the people who have a heart attack will die suddenly of an arrhythmia," he says. "This is because once your heart is structurally diseased, it is much more likely to be electrically unstable."

The most common way to die in our society is from heart disease, Anderson points out. Most of today's drugs for fighting heart disease indirectly target protein receptors on the cell membrane. In contrast, this study provides insights into how we might more directly target signaling molecules inside the cell. This research reflects only a tiny fraction of the possible targets to be explored by scientists in the years ahead.

"We don't know if inhibiting CaM kinase will make people live longer, but these kinds of studies suggest the possibility that it will."

Drug discovery begins at the bench of scientists such as Anderson. This basic research, which serves as an early step in getting industry excited about developing new classes of drugs, is made possible only through funding from the National Institutes of Health (NIH), and those funds are dwindling.

Anderson says it is important for us to communicate with our elected representatives to let them know we support funding for NIH. "If that money goes away, then the discoveries that lead to new therapies will go away too."

Resources:

“Discovery has implications for heart disease.”

“Discovery could lead to new drug targets for heart disease.”