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New Role for Heart Response Enzyme May Yield Heart Failure Therapy

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Duke Health News 919-660-1306

Durham, N.C. -- Duke University Medical Center researchers
have identified a new protein that plays a critical role in
enabling the heart to respond to such external stimuli as
exercise or stress, as well as in the progressive loss of heart
function that is heart failure, the researchers said.

Their findings, they said, suggest new approaches to prevent
or reverse heart failure, which affects two to three million
people in the U.S. The team reports its findings in the August
2005 issue of Nature Cell Biology.
The study is now available as an advance online
publication.

"We've uncovered new details of the first step of heart
failure, in which heart receptors that normally allow the heart
to adapt in the face of changing conditions are lost, rendering
the heart unable to pump enough blood to meet the needs of the
body's other organs," said cardiologist and geneticist Howard
Rockman, M.D., of Duke. "If we could prevent this loss of heart
receptors, we might improve heart function in patients with
heart failure."

The enzyme the researchers studied, called phosphoinositide
3-kinase (PI(3)K), governs the function of beta-adrenergic
receptors on the surface of heart cells. Such receptors are
protein switches that nestle in the cell membrane and that are
activated by the hormone adrenaline to enhance the heart's
pumping action in response to exercise or stress.

In heart failure patients, chronic stress leads to an excess
of adrenaline, over-stimulating beta-adrenergic receptors, a
process that results in receptor desensitization and loss,
Rockman said.

Earlier work by Rockman's team identified PI(3)K as being
required for beta-adrenergic receptors to be drawn back into
the cell for recycling once they have been activated. Those
studies showed that increases in PI(3)K underlie the loss of
beta-adrenergic receptors in animals and patients with heart
failure, Rockman said.

The researchers' earlier experiments showed that disrupting
the function of PI(3)K preserves beta-adrenergic receptors on
heart cells when they are chronically exposed to adrenaline and
thus preserves heart function. However, it has remained unclear
exactly how the heart enzyme exerts its effects on the heart
receptors, Rockman added.

The researchers' experiments revealed that PI(3)K plays
multiple roles as an enzyme that affect heart responses. It
manufactures signaling molecules called phospholipids in the
cell. And it activates other molecules, among them one called
"non-muscle tropomyosin," which plays an important role in
maintaining cell structure. In both cases, PI(3)K functions by
attaching a phosphate group to the molecule to be activated, a
process called phosphorylation.

By preventing activation of tropomyosin by PI(3)K in cells,
the researchers prevented heart receptors from leaving the cell
surface, thereby blocking the initial step that occurs during
heart failure. Also, the researchers reported, when they
eliminated tropomyosin activity altogether, they also
maintained heart receptors.

"These studies demonstrate a previously unknown role for the
protein phosphorylation activity of PI(3)K in receptor
internalization and identify non-muscle tropomyosin as an
important substrate of the enzyme's activity," Rockman said.
"The findings may offer a new approach to the treatment of
heart failure."

Drugs that selectively prevent PI(3)K from activating
tropomyosin -- either by modifying tropomyosin or inhibiting
PI(3)K's enzymatic activity -- might effectively block heart
receptor loss to maintain or restore normal heart function in
those at risk or suffering from heart failure, he added.

Collaborators on the study include Sathyamangla Naga Prasad,
Arundathi Jayatilleke and Aasakiran Madamanchi, all of Duke.
The work was supported by the National Institutes of
Health.

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