Molecule Turns On Genes That Lead To Heart Failure
Researchers at the Center for Translational Medicine at Thomas Jefferson University have found a second signaling molecule they believe plays an important role in heart failure, and this one works in a way not seen before.
In the online issue of the Proceedings of the National Academy of Sciences (PNAS), the scientists describe how, in experimental mice, an enzyme known as GRK5 normally present in cardiac cell membranes, enters the cell’s nucleus. There it turns on genes that push a stressed heart to grow larger, leading to failure of the organ to adequately pump blood.
The finding is significant for two reasons, says Jeffrey Martini, Ph.D., a postdoctoral researcher who is the study’s lead author. He says that, clinically, GRK5 could possibly provide a new target for agents to treat the disorder, which affects more than five million Americans, according to the American Heart Association.
“We are now looking for ways to use a small molecule to either inhibit GRK5 from going inside the cell’s nucleus or to stop its activity once inside the nucleus,” Dr. Martini says. “It could be a very novel approach to treating this disease.”
The second reason is because the study advanced the scientific understanding of how a certain class of protein signals affects cardiac cells – and, possibly, all other cells in the body, he says.
Up until now, researchers believed that GRKs – which are G protein-coupled receptor kinases – worked only at the cell membranes. G protein-coupled receptors span a cell’s membrane; they bind with hormones from outside of the cell causing a molecular change inside the cell. GRKs shut down activity of these receptors.
Walter Koch, Ph.D., the study’s senior investigator and director of the Center for Translational Medicine, has characterized how these GRKs work in heart failure, and has found that one, GRK2, is critically important in heart function. It helps desensitize heart tissue to stress hormones that bind to the membrane receptors, and when GRK2 is elevated in the heart, patients have more severe heart failure. Based on the discovery that an inhibitor for GRK2 can prohibit heart failure in experimental animals, Dr. Koch is now working on a drug for heart patients.
Martini and the research team discovered that GRK5 has a dual – as well as contradictory – role in heart failure. Preliminary evidence seems to show that it can work at the cell membrane to protect against heart failure, but this study demonstrated how GRK5 moves from the cell membrane and travels into the nucleus to change gene expression that pushes hypertrophy (an increase in size) of heart tissue. “Our current studies are investing the mechanism of GRK5 nuclear entry and we are developing inhibitors to prevent this action.”” he says.
The finding expands the potential function of GRKs, which are active in many cells in the body, Dr. Martini notes. “The novelty of the paper is that a group of kinases traditionally thought to work by turning off receptors at the membrane of a cardiac cell has an alternative function inside the nucleus and is able to directly regulate genes,” he says.
“While we demonstrated how important this in the heart, it probably is working in the same way in other cell types, and that is an exciting finding.”
The study was funded by grants from the National Institutes of Health, a Great Rivers Affiliate of the American Heart Association Predoctoral Fellowship, and a Commonwealth of Pennsylvania Department of Health Grant.