Molecule Found To “Turn On” Genes That Lead To Heart Failure, Jefferson Scientists Show
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 August 18, 2008 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.
Media Only Contact:
Richard Cushman
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 8/19/2008