Protein Targeting Observed to Improve Heart Failure Symptoms


Increasing phosphate binding to a protein receptor could increase cardiac output in patients with heart failure.

Findings from a new study suggest that an investigational drug may target proteins that help cardiac muscles contract, which could help to improve cardiac output among patients with heart failure.

The drug was able to bypass dysregulated cell signaling pathways and directly induce contractions in the heart muscle. In the study published by Science Advances, the authors discovered that modifying myosin binding protein-C (MyBP-C) significantly improved cardiac output in mice.

This new study provides the first evidence that protein targeting may be an effective way to improve heart function among humans with heart failure, according to the authors.

The MyBP-C protein is located inside of contractile machinery of cardiomyocytes, which keep the heart pumping blood throughout the body. The protein contains 3 locations where phosphate groups bind to, according to the study. Once the phosphate groups attach, the protein helps the heart contract vigorously in stressful situations.

The study authors aimed to determine which of 3 phosphate attachment sites enhance the heart’s contractions the most. By discovering this, the authors could then directly target the site to improve heart function.

“Phosphorylation of MyBP-C enhances both the magnitude and rate of cardiomyocyte contraction, which at the whole heart level translates to enhanced systolic left-ventricular pressures, and ultimately cardiac output,” said lead researcher Julian E. Stelzer, PhD. “Our findings show that a specific amino acid on MyBP-C, serine 302, can be directly targeted to enhance the rate and magnitude of cardiac pump function, which would be of benefit to a large number of heart failure patients.”

The authors created mice models with MyBP-C modified at amino acids where phosphates attach to highlight the important binding sites, according to the study.

The mice models in which only the serine 302 binding site modified were observed to lack maintenance of systolic blood pressure. This group was found to have significant reductions in blood supply to outer tissues, which is similar to heart failure in humans.

The authors determined that serine 302 is crucial for the heart to effectively pump blood, according to the study.

For manufacturers interested in creating heart failure drugs, these findings indicate that targeting serine 302 on MyBP-C may be a beneficial starting point.

Additionally, these findings suggest how hearts respond to stress — phosphate groups are added to MyBP-C by protein kinase A (PKA). The authors were able to determine the effects of phosphate group attachment to specific locations on MyBP-C, and how each attachment altered function.

“We found that the functional effect of preventing phosphorylation of serine 302 alone, is equivalent to the impact observed by preventing phosphorylation of all three PKA phosphorylatable sites in MyBP-C, which pinpoints serine 302 as the main molecular target of PKA phosphorylation in MyBP-C for cardiac muscle contraction,” said lead study author Ranganath Mamidi, PhD.

The authors explored the targeted method in isolated cardiac muscle fibers and mouse hearts.

“In the intact heart, phosphorylation of serine 302 increased the rate and magnitude of pressure development, and therefore cardiac output, but this effect was abolished in mice with modified serine 302 MyBP-C,” Dr Mamidi said. “Therefore, our studies have identified a critical downstream target of stress signaling that can modulate cardiac output in vivo.”

These findings show that drugs that increase phosphate binding to serine 302 on MyBP-C could dramatically improve cardiac output in patients with heart failure, according to the study.

“Now that serine 302 in MyBP-C has been identified as a molecular target to boost cardiac performance, efforts are underway to design small molecules that can elicit similar functional effects in the intact human heart,” Dr Stelzer concluded.

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