Posted December 11, 2013

Temple researchers uncover new possibilities in heart therapeutics

Two recent studies involving Temple researchers in the School of Medicine have shed light on the prospects of new therapies for patients who have sustained heart attacks or are suffering from the effects of heart disease.

In the first study, which appeared online in the journal Science Signaling, the researchers discovered that two of the most commonly prescribed drugs for the treatment of heart failure—beta-blockers and nitrates—might help failing hearts by counteracting the effects of an enzyme called GRK2, which can trigger the death of heart cells.

Led by Walter J. Koch, W.W. Smith Chair in Cardiovascular Medicine—professor and chair of pharmacology in the School of Medicine, and professor and director of the Center for Translational Medicine—the researchers explored whether nitric oxide, which protects the heart from damage caused by ischemia (blocked blood flow to heart tissue), might reduce the effects of GRK2.

Koch and his collaborators found that introducing a mutation in GRK2 prevented the positive effects of nitric oxide by prohibiting it from binding to that enzyme. As a result, the extent of heart injury increased dramatically. Further, drugs designed to deliver nitric oxide to the heart were ineffective when the mutation was present, indicating that that binding activity is key for those drugs to ensure proper blood flow to the heart.

The findings also suggest that the nitric-oxide-delivering drugs, which carry and then release those molecules in targeted tissues, might be key in the treatment of heart failure. However, few such drugs are available for clinical use.

Nitric oxide has been shown to control the widening of blood vessels, which has long been thought the benefit of using existing heart-failure therapies, such as beta-blockers and nitrates. But Koch’s research shows that those drugs may be most effective by blocking GRK2 activity, a previously unknown mechanism.

In the second study, published in Science Translational Medicine, Temple researchers in the Cardiovascular Research Center and the Center for Translational Medicine, collaborated with the pharmaceutical company GlaxoSmithKline to determine whether or not it is possible to use a drug to limit the extent of damage sustained from a heart attack.

The researchers found that activity of a heart protein called TNNI3K is elevated in patients who suffer from heart failure, which can develop in the years after a heart attack.

When TNNI3K was overproduced in research models, it promoted the injury of heart tissue due to the blockage of blood flow to the heart during an attack, and once blood flow returned after an attack. The opposite occurred in models in which TNNI3K had been deleted—injuries to the heart were limited, and heart function was better.

Researchers from Temple and GlaxoSmithKline identified compounds that could block TNNI3K activity. Treatment with those compounds after heart attacks preserved heart function markedly, producing effects that were similar to those found in models without TNNI3K.

A major aim of the Center for Translational Medicine at Temple is to facilitate the delivery of new medicines to patients in the clinic, which might happen with TNNI3K inhibitors if they are proven safe and effective.