Signaling Protein Helps Limit Damage in Heart Attack, Jefferson Scientists Show
Scientists
at the Center for Translational Medicine at Thomas Jefferson University
in Philadelphia have shown that a specific signaling protein is crucial
to protecting the heart and helping it to adapt during a heart attack.
The
protein Gi is known to have increased activity in the failing heart,
but researchers have never been sure if it was helping the heart adapt
to damage or if it was actually causing more heart cells to die. The
Jefferson team, led by Walter Koch, Ph.D., W.W. Smith Professor of
Medicine and director of the Center for Translational Medicine in the
Department of Medicine at Jefferson Medical College, experimentally
blocked the protein in the hearts of genetically engineered mice
experiencing heart attacks. They found that the animals had greater
heart damage than did similar mice with a working protein. The team
reports its findings March 18, 2008, in the journal Circulation.
Gi
is important in intracellular signaling, akin to a molecular switch,
Dr. Koch notes. It’s not a new drug target, he explains, but the
activation of some receptors (such as beta-2 adrenergic receptors) that
also turn on Gi could be targets.
Developing
a “class-specific Gi inhibitor,” Dr. Koch explains, is an important
step to understanding Gi’s role and behavior. “We don’t have to worry
about what receptor we are blocking; we’re blocking a receptor that
couples with Gi. We never had the tools before to tell if Gi activation
was good or bad. We think that we can now begin to test the role of Gi
in cardiac injury.”
In
the work, Dr. Koch’s group developed a transgenic mouse with a
“functional knockout” of the Gi gene, meaning that it lacked a working
gene. The scientists then simulated a heart attack, catheterization and
reperfusion by tieing off a coronary artery for 30 minutes and
subsequently reestablishing the blood flow, causing an inflammatory
response and tissue damage.
“It
appears that in this setting, Gi is an important protective mechanism,”
Dr. Koch says. “The heart wants to activate Gi and attempt to protect
cardiac myocytes from dying. We found that in this acute setting, heart
attacks are bigger when Gi is blocked.” As a result, the heart can’t
pump as well.
They
would like to find out Gi’s role in chronic heart failure, where there
is much less cell death occurring, and Gi levels remain high. In the
chronic phase, Dr. Koch points out, Gi activity could be “maladaptive.”
They plan to test the idea in chronic heart failure animal models.
Media Only Contact:
Ed Federico
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 3/18/2008