Disrupted recycling of proteins found to damage heart health

In the study, researchers found that low levels of an enzyme called ‘ubiquitin-specific peptidase 5’, or USP5, lead to the build-up of proteins in heart muscle cells, triggering 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 Centre for Cell & Molecular Biophysics at King’s College London BHF Centre of Research Excellence. The findings were published in Science Advances.

USP5’s protective powers

Maintaining the balance of new proteins and breaking down old or faulty ones in the heart is important for heart health. The body has specialised 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 function of the heart, leading to heart disease.

“Heart disease caused by the accumulation of non-functional protein “junk” (proteinopathies) are common causes of heart failure. There are no causal therapies for these diseases. Identifying novel pathways to target the root cause — the accumulation of misfolded protein “junk” — could alleviate many of these conditions,” says Professor Mathias Gautel, Professor of Molecular Cardiology at King’s and co-author on 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 cleaved off and broken down, ready to be used again. USP5 plays a crucial role in recycling the ubiquitin tag, ensuring a balance between the generation and breaking down of proteins.

In the search for new therapeutic approaches, the researchers at MPI HLR demonstrated that, in mouse models, low USP5 levels cause dilated cardiomyopathy — a condition where one or both heart chambers become enlarged, 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,” says Dr Silke Kreher, postdoctoral researcher at MPI HLR and co-lead author of the paper.

“Using magnetic resonance imaging (MRI), we showed that these animals had significantly enlarged hearts and severely 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 the levels of USP5 in cell cultures and mouse models of cardiomyopathy, the heart cells were cleared of the protein “junk.” 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 like high blood pressure. These experiments built on the expertise of the Gautel lab in studying faulty proteins implicated in heart disease.

A potential therapeutic target

“Our study highlights the role of ubiquitin chain recycling in dilated cardiomyopathy, for which USP5 is essential, for the first time. We assume that inhibiting the loss of USP5 or therapeutically increasing USP5 concentration in heart muscle cells will reduce protein aggregation and thereby at least slow the progression of the disease,” says Professor Thomas Braun from the MPI HLR, senior author of the study.

The researchers emphasise 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 leading to USP5 protein loss in dilated cardiomyopathy.

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