To prove this novel conclusion, the research team used gene therapy to inhibit the small protein, kinase known as G protein-coupled receptor kinase 2 (GRK2), and found heart muscles cells in mice were substantially protected against destruction that would otherwise occur after an induced myocardial infarction (MI), or heart attack.
Conversely, mice engineered to express excess GRK2 had more damage than would have been expected after an MI, the researchers say in the article currently found online at Circulation Research and to be published in the October 29th issue.
These finding suggest that humans experiencing a heart attack might be helped with delivery of a therapeutic targeting inhibition of GRK2, says Walter J. Koch, Ph.D., Director of the Center for Translation Medicine at Jefferson.
"Our results clearly show that GRK2 promotes cell death after a heart attack, so an inhibitor of this molecule is likely beneficial in preventing permanent damage, if delivered quickly enough," he says. "Currently, we have a gene therapy approach but for this indication a small molecule would be preferred."
Dr. Koch says that while it may be years before this concept can be tested in patients experiencing an MI, he expects anti-GRK2 gene therapy will be tested in patients with heart failure much sooner. A Phase I clinical trial for GRK2-targeted gene therapy is preparing to be launched, pending federal approval.
Dr. Koch and his colleagues have been working for 15 years to link GRK2 to heart failure in patients. They have demonstrated that the protein puts a brake on the beta-adrenergic receptors that respond to hormones (adrenalin and noradrenalin) that drive the heart beat – the rate and force of contractile function in heart cells. This braking action is enhanced in chronic heart failure, and relieving it by inhibiting activity and expression of GRK2 allows the heart to work better, the researchers have shown in animal studies using gene therapy.
The question they looked at in this study is whether GRK2 plays any role after a heart attack. Most cardiology researchers theorized that it was protective, because expression of the protein is increased by three to four times immediately after a heart attack, Dr. Koch says. "People always thought that GRK2 was working to shut off beta receptors because injured hearts were pumping out too much adrenaline, and that this blocking of over activity in an injured heart is protective."
But what the researchers discovered is that over production of GRK2 following a heart attack actually stimulates pro-death pathways in myocyctes (heart cells) outside of the initial zone of damage. They specifically found an inverse link between GRK2 activity and the production of nitric oxide (NO), a molecular messenger that protects the heart against damage caused by a sudden loss of blood. "When there is more GRK2, there is less NO, and vice versa," Dr. Koch says. They believe that GRK2 may be affecting NO production by inhibiting the prosurvival protein kinase Akt, which itself regulates NO. (more)
The mice MI studies then proved that inhibiting GRK2 protected heart cells, Dr. Koch says.
"Our results clearly show that GRK2 is a pathological target in the heart, involved in both progressive heart failure and in death of heart cells after a heart attack," he says.
The study was supported in part from grants from the National Institutes of Health and the American Heart Association.
Rick Cushman | EurekAlert!
A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
18.08.2017 | Life Sciences
18.08.2017 | Physics and Astronomy
18.08.2017 | Materials Sciences