‘Decoy’ peptide shows promise for preventing heart failure

April 18, 2021

An osteoporosis treatment is showing promising results in mice. (AP Photo/Robert F. Bukaty)

Researchers have developed a compound that blocked an important regulator of heart failure in mice, which could pave the way toward future therapeutics for the often fatal condition.

The regulator in question is the protein GRK5, a key troublemaker in the development of heart failure that usually dwells in the outer membrane of heart cells but responds to stress by relocating to the cell nucleus, where it turns on genes that cause the heart to thicken. In a study published March 30 in Science Signaling, the researchers found that by stopping GRK5 from reaching the nucleus, they could block this process and improve heart health in a mouse model of heart failure.

When the heart is put under added strain, from high blood pressure or damage from a heart attack, for example, it grows thicker to compensate. But over time, the heart muscle can become stiff, which reduces its blood-pumping capacity and causes heart failure. This condition affects about 6.2 million people in the U.S., according to the Centers for Disease Control and Prevention, causing shortness of breath, fatigue and weakness and often, death

To thwart GRK5 from instigating heart failure, the researchers looked at its accomplice, a protein called calmodulin, which enables GRK5 to migrate to the nucleus when the two bind together. They developed a truncated version of GRK5, a peptide called GRK5nt, which binds to calmodulin but doesn't turn on heart failure genes. 

GRK5nt acts "kind of as a decoy protein, or you could call it a 'calmodulin sponge,'" said Wally Koch, lead author of the study and a professor of pharmacology and translational medicine at the Lewis Katz School of Medicine at Temple University. The researchers hypothesized that GRK5nt would reduce heart failure by mopping up calmodulin, leaving little available to assist GRK5 migration to the nucleus.

To see how this decoy peptide fared in a mouse model of heart failure, the researchers genetically modified mice to express GRK5nt in addition to regular GRK5. They compared them with control mice, which produced only GRK5. 

Some of the mice received a type of surgery commonly used to study heart failure in animals: "Basically, you tie a knot into the aorta, right above the heart," Koch explained. By constricting this artery, which delivers blood from the heart to the rest of the body, the surgery puts additional pressure on the heart, similar to that experienced by people with high blood pressure. Another subset of the mice received a sham, or placebo, surgery. 

Eight weeks after surgery or the sham equivalent, the team measured the animals' heart function. Among the controls, the mice that received surgery had thicker hearts that pumped blood less effectively than those that received the sham procedure. But in the genetically modified animals that expressed the decoy peptide, these negative effects of the surgery were lessened. 

After surgery, high levels of GRK5 were found in the nuclei of heart cells in control mice, but not in the mice expressing the decoy peptide, suggesting that the peptide stopped the protein from reaching the nucleus. 

"So our hypothesis was true," Koch said. "If you actively keep GRK5 out of the nucleus, it leads to beneficial effects."

The researchers also looked to see if GRK5nt had any ill effects in animals that received sham surgery. 

"Importantly, when we made these mice and they had this decoy protein expressed in the heart cells, it didn't change the baseline [heart] function; it didn't cause any pathology by itself, which is good," Koch said. 

They also examined whether expression of calmodulin-mopping GRK5nt disrupted other cellular processes that rely on calmodulin. Koch said the team showed that the peptide did not affect such processes, but acknowledged, "We didn't do an exhaustive search."

According to Koch, the peptide holds promise as a future therapeutic for people at risk of heart failure. But first, the researchers need to test whether GRK5nt is effective as a treatment. In the current study, the peptide was present in the animals from birth. 

"The next step is to see if we could take an animal that's sick and treat it," Koch said.

The study, "A peptide of the N terminus of GRK5 attenuates pressure-overload hypertrophy and heart failure," published March 30 in Science Signaling, was authored by Ryan C. Coleman, Akito Eguchi, Melissa Lieu, Rajika Roy, Eric W. Barr, Jessica Ibetti, Anna-Maria Lucchese, Amanda M. Peluzzo, Kenneth Gresham, J. Kurt Chuprun and Walter J. Koch, Lewis Katz School of Medicine at Temple University.

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