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Temple researchers uncover clues to how existing heart drugs work
Date:11/5/2013

(Philadelphia, PA) Some of the most commonly prescribed drugs for the treatment of heart failure are beta-blockers and nitrates, which help to relax blood vessels and decrease the heart's workload. The drugs were thought to produce those effects through distinct molecular pathways, but according to a new study led by scientists at Temple University School of Medicine, both types of drugs may help the failing heart by counteracting the effects of an enzyme known as GRK2. The findings suggest that new drugs aimed specifically at GRK2, which can trigger the death of heart cells, could protect the heart from progressive disease.

The study, which appears online October 29 in the journal Science Signaling, describes a previously uncharacterized interaction between GRK2 and an enzyme called endothelial nitric oxide synthase (eNOS), in which the two enzymes attempt to block one another's activity, with different outcomes on heart function.

"When eNOS is activated, GRK2 is inhibited, and good things happen [to the heart]," explained senior investigator Walter J. Koch, PhD, Professor and Chair of the Department of Pharmacology at Temple's School of Medicine and Director of the Center for Translational Medicine. In heart disease, however, the balance is flippedGRK2 is activated and eNOS is inhibited, which results in heart cell death and a loss in contractile function.

At the center of the GRK2 and eNOS interaction is nitric oxide (NO), the production of which is controlled by eNOS. Nitric Oxide protects the heart from damage caused by ischemia, or blocked blood flow to heart tissue. Exactly how it exerts its cardioprotective effects, however, has been a mystery.

To determine whether cardioprotection by NO was linked to GRK2 inhibition, Koch and colleagues conducted a series of experiments in mice. The most pivotal of those experiments involved the development of a novel "knock-in" mouse model in which a point mutation was intr
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Contact: Jeremy Walter
Jeremy.Walter@tuhs.temple.edu
215-707-7882
Temple University Health System
Source:Eurekalert

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