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New Insight into Heart Failure Suggests Novel Drug Target

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Duke Health News 919-660-1306

DURHAM, N.C. -- By disrupting the activity of a single heart
protein, Duke University Medical Center researchers eased heart
failure significantly in mice with chronic high blood pressure.
The finding provides new insight into the root causes of the
progressive decline in cardiac function that is heart failure
and suggests a novel method to prevent the deterioration.

"Despite newer therapies to treat heart failure, patient
mortality rates remain high, indicating a need for novel
treatment strategies that complement current methods," said
Howard Rockman, M.D., professor of medicine and senior author
of the study. "The current study elucidates a key cellular
mechanism that underlies heart failure and identifies a
promising new method for stalling the progression of the
disease."

The team reports its findings in the October 1, 2003 issue
of The Journal of Clinical
Investigation
. The research was funded by the National
Institutes of Health, the Burroughs Wellcome Fund and the
Stanley J. Sarnoff Endowment for Cardiovascular Science.

The researchers studied beta-adrenergic receptors on the
surface of heart cells, which modify the activity of the heart
in response to the hormone adrenaline. These receptors --
protein switches that nestle in the cell membrane -- control
the heart's ability to pump blood to the tissues of the body in
response to such environmental situations as exercise or
stress.

In heart failure patients, chronic stress leads to an excess
of adrenaline, thereby over-stimulating beta-adrenergic
receptors, a process that results in receptor desensitization
and loss, Rockman said. Cardiologists have long debated whether
the loss of beta-adrenergic receptors characteristic of heart
failure protects the heart or whether it contributes to the
disease, he added.

Earlier work conducted by Rockman's team identified a
protein enzyme, called PI3Kgamma, which is required for the
internalization and recycling of beta-adrenergic receptors on
heart cells. Disrupting the function of PI3Kgamma preserves
beta-adrenergic receptors on heart cells when they are
chronically exposed to adrenaline, Rockman said.

However, whether the manipulation would maintain heart
receptors in a living animal was unclear, as were the
consequences of such an intervention for the failing heart. "If
we prevent beta-adrenergic receptors from being internalized,
what happens to heart function? Is it better or worse?" Rockman
asked.

In the new study, the researchers genetically manipulated
mice to produce an inactive form of PI3Kgamma, which shut down
the protein's ability to trigger beta-adrenergic receptor loss.
Thus, in the genetically altered mice, beta-adrenergic
receptors remained active when chronically exposed to an
adrenaline-like chemical, while the receptors of normal mice
exhibited a substantial loss of function as occurs in heart
failure patients, they found.

Moreover, after three months of chronic pressure overload,
mice with the inactive heart protein exhibited less than half
the decline in heart function compared to mice with the active
protein, the team reported. The mutant mice with high blood
pressure also survived longer than normal mice with the same
condition.

"Our study results show that an intervention that maintains
functional beta-adrenergic receptors on the heart surface by
disrupting PI3Kgamma activity leads to improved heart function,
a result supporting the idea that the loss of receptors
contributes to heart failure," Rockman said. "These findings
identify a potential new target for heart drugs and may have
important clinical implications."

The research team included Jeffrey Nienaber, M.D., a
surgical fellow and primary author of the study, Hideo
Tachibana, M.D., Sathyamangla Naga Prasad, Ph.D., and Lan Mao,
M.D., all of Duke. Other participants include Giovanni
Esposito, M.D., of Federico II University in Naples, Italy and
Dianqing Wu, Ph.D., of the University of Connecticut Health
Center in Farmington.

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