Research is discovering enzymes that are essential for maintaining heart health

Research is discovering enzymes that are essential for maintaining heart health

A new study has identified an enzyme that plays an important role in absorbing unnecessary or damaged proteins in the heart - an important process in maintaining heart health.

In the study, researchers found that low levels of an enzyme called ubiquitin-specific peptidase 5, or USP5, led to the buildup of proteins in heart muscle cells and triggered a type of heart disease called dilated cardiomyopathy in animal models.

The study was led by the Max Planck Institute for Heart and Lung Research (MPI HLR) and involved researchers from the Randall Center for Cell & Molecular Biophysics at King's College London BHF Center of Research Excellence. The results were published inScience advances.

USP5 -protective forces

Maintaining the balance of new proteins and building up old or faulty ones in the heart is important for heart health. The body has special waste management factories (called proteasomes) that break down proteins when they become damaged or are no longer needed. But when this process goes wrong, proteins can build up and impair the heart's function, leading to heart disease.

Heart disease caused by the accumulation of non-functional protein “junk” (proteinopathies) is a common cause of heart failure. There are no causal therapies for these diseases. Identifying novel pathways to the root cause – the accumulation of misfolded protein “junk” – could alleviate many of these conditions. “

Professor Mathias Gautel, Professor of Molecular Cardiology at King's and co-author in the study

When proteins are ready to be broken down, they are “tagged” with a molecular marker called ubiquitin so they can be transported to the proteasome. Before the protein enters the proteasome, the ubiquitin tag is held and broken off to be used again. USP5 plays a crucial role in recycling the ubiquitin tag to ensure a balance between protein generation and degradation.

In the search for new therapeutic approaches, MPI HLR researchers showed that in mouse models, low levels of USP5 cause dilated cardiomyopathy - a condition in which one or both chambers of the heart enlarge, reducing their ability to contract.

"Using genetic manipulation, we specifically deactivated USP5 in the heart muscle cells of adult animals. When USP5 was missing, the animals developed dilated cardiomyopathy as a result" paper.

“Using magnetic resonance imaging (MRI), we showed that these animals had significantly enlarged hearts and greatly reduced pumping capacity,” adds Yvonne Eibach, doctoral researcher at MPI HLR and co-lead author of the paper.

The researchers showed that when they increased USP5 levels in cell cultures and mouse models of cardiomyopathy, the heart cells were cleared of the “garbage” protein. Mice with increased levels of USP5 were able to cope better when their hearts were placed under increased pressure stress, which is seen in conditions such as high blood pressure. These experiments draw on the Gautel laboratory's expertise in studying faulty proteins involved in heart disease.

A potential therapeutic target

"Our study shows the role of ubiquitin chain recycling in dilated cardiomyopathy, for which USP5 is essential for the first time. We assume that the progression of the disease is slow," says Professor Thomas Braun from MPI HLR, senior author of the study.

The researchers emphasize that extensive further research is needed to determine whether USP5 could be a target for drug development. As next steps, the teams plan to investigate the mechanisms that lead to USP5 protein loss in dilated cardiomyopathy.

“If effective and practical ways can be found to alter USP5 levels in heart cells, starting from cell and animal models, this could pave the way to developing new therapies against a wide range of heart diseases,” adds Professor Gautel.

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