Scientists Show Protein Plays Critical Role in Heart Failure in Both the Heart and Adrenal Gland
A protein that plays an important regulatory role in heart failure in the heart also exerts powerful effects on the adrenal gland, Jefferson Medical College researchers have found. The protein, GRK2, is a potential drug target for heart failure.
Walter Koch, Ph.D., director of the Center for Translational Medicine in the Department of Medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia, and his co-workers had showed previously that GRK2, or G-protein coupled receptor kinase 2, is increased in the heart in heart failure, and shuts off certain receptors called beta-adrenergic receptors, desensitizing them.
When the heart is failing, the body’s sympathetic nervous system, which kicks into gear in the so-called fight or flight response, goes to work, releasing catecholamines – hormones such as epinephrine and norepinephrine in an ill-conceived attempt to stimulate the heart.
Catecholamines are released from two sources – nerve terminals and from the adrenal gland, from which they enter the circulation. Dr. Koch and his co-workers wondered if GRK2 and alpha 2-adrenergic receptor function were affected in the adrenal gland as well. They subsequently looked at adrenal glands from mice in heart failure, and found that GRK2 was increased.
According to Dr. Koch, when neurons release catecholamines, a feedback system that works through alpha 2-adrenergic receptors “is the brake on the system.” They found that mice in heart failure had high levels of GRK2 in the chromaffin cells in the adrenal gland, which caused the downregulation and desensitization of alpha 2 adrenergic receptors.
“Basically, the brake is being shut off,” he says. “We found that catecholamine release was high in adrenal cells in heart failure, and GRK2 appears to be the mechanism.” The researchers report their results November 14, 2005 at the American Heart Association’s Scientific Sessions 2005 in Dallas.
When the scientists reduced GRK2 levels using an inhibitory peptide, ßARKct, catechomine release went down and the alpha 2-receptor function was restored, he notes. It appears that the increased GRK2 is a mechanism for catecholamine release, and contributes to the high catecholamines in heart failure. “The findings show that not only is GRK2 a target in the heart for heart failure, but also in the adrenal gland,” he says.
Next, Dr. Koch’s group is going to use gene therapy in the adrenal gland to decrease GRK2 activity and try to find out whether or not targeting the protein only in the adrenal gland will affect heart function simply by lowering catecholamines.
Steve Benowitz | EurekAlert!
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