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Recent research has discovered an enzyme that is essential for the breakdown of unnecessary or damaged proteins in the heart, which is crucial for maintaining heart health.
According to the study, researchers observed that low levels of an enzyme known as ‘ubiquitin-specific peptidase 5’, or USP5, result in the accumulation of proteins within heart muscle cells. This buildup can lead to a form of heart disease called dilated cardiomyopathy in animal subjects.
The research was conducted by the Max Planck Institute for Heart and Lung Research (MPI HLR) with assistance from the Randall Centre for Cell & Molecular Biophysics at King’s College London BHF Centre of Research Excellence. The results were published in Science Advances.
The protective role of USP5
It is vital to balance the creation of new proteins with the degradation of old or faulty ones in the heart for overall heart health. The body utilizes specialized structures known as proteasomes to remove proteins that are damaged or no longer necessary. If this system fails, protein accumulation occurs, which can disrupt heart function and lead to disease.
“Heart disease that arises from the buildup of dysfunctional protein ‘junk’ (proteinopathies) frequently leads to heart failure. Currently, there are no therapies that address the root causes of these issues. Discovering new pathways to target the underlying problem — the accumulation of misfolded protein ‘junk’ — could help many patients,” states Professor Mathias Gautel, a Professor of Molecular Cardiology at King’s and co-author of the study.
When proteins are set to be dismantled, they receive a marker called ubiquitin, which helps them reach the proteasome. Before these proteins enter the proteasome, the ubiquitin tag is removed and recycled for future use. USP5 is vital for this recycling process, maintaining a healthy balance of protein production and degradation.
In their pursuit of novel treatment strategies, the MPI HLR researchers established that low levels of USP5 in mouse models lead to dilated cardiomyopathy, a disorder characterized by the enlargement of heart chambers and a decline in their contracting ability.
“We used genetic techniques to selectively turn off USP5 in the heart muscle cells of adult mice. The absence of USP5 resulted in the development of dilated cardiomyopathy in these animals,” explains Dr. Silke Kreher, a postdoctoral researcher at MPI HLR and a co-lead author of the study.
“MRI scans revealed that these animals had significantly larger hearts and a greatly diminished ability to pump blood,” adds Yvonne Eibach, a doctoral researcher at MPI HLR and co-lead author of the study.
The researchers also discovered that increasing USP5 levels in both cell cultures and mouse models of cardiomyopathy helped eliminate the protein “junk.” Mice with elevated USP5 levels managed better under conditions of heightened blood pressure stress. These findings leveraged the Gautel lab’s expertise in exploring malfunctioning proteins related to heart disease.
A promising therapeutic target
“This study is the first to highlight the importance of recycling ubiquitin chains in dilated cardiomyopathy, which depends on USP5. We believe that preventing the loss of USP5 or boosting its levels in heart muscle cells could reduce protein accumulation and at least slow disease progression,” says Professor Thomas Braun, senior author of the study from MPI HLR.
The team stresses the need for extensive further investigations to determine the potential of USP5 as a drug development target. Future research will focus on exploring the mechanisms that lead to the loss of USP5 protein in dilated cardiomyopathy.
“Should we find effective methods to adjust USP5 levels in heart cells, starting from studies in cell and animal models, it could open up avenues for new treatments for a variety of heart conditions,” concludes Professor Gautel.
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