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New Insight Into Heart Failure Suggests Novel Drug Target

Date:
October 2, 2003
Source:
Duke University Medical Center
Summary:
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.

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.

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"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 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.


Story Source:

The above story is based on materials provided by Duke University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Duke University Medical Center. "New Insight Into Heart Failure Suggests Novel Drug Target." ScienceDaily. ScienceDaily, 2 October 2003. <www.sciencedaily.com/releases/2003/10/031002055520.htm>.
Duke University Medical Center. (2003, October 2). New Insight Into Heart Failure Suggests Novel Drug Target. ScienceDaily. Retrieved March 31, 2015 from www.sciencedaily.com/releases/2003/10/031002055520.htm
Duke University Medical Center. "New Insight Into Heart Failure Suggests Novel Drug Target." ScienceDaily. www.sciencedaily.com/releases/2003/10/031002055520.htm (accessed March 31, 2015).

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