An unexpected finding that links a structural heart protein to gene regulation following heart stress suggests potential new avenues for developing heart failure therapies.
The work focuses on a protein called junctophilin-2 (JP2). Previous work from the lab has shown that JP2 is a structural protein that is essential for heartbeat, and that loss or disruption of JP2 is associated with heart failure.
The new study conducted in mice and published in the journal Science that under stress conditions, JP2 is cleaved into two fragments. This breakdown of JP2 damages the structural architecture of the cells and disrupts heart cell function. The new study's surprising finding is that one of the newly created fragments of JP2 protects the heart from damage by traveling to the heart cells' nuclei and turning off the expression of genes that promote heart failure.
To prove the beneficial effect of the JP2 fragment, the researchers engineered mice with increased levels of the JP2 N-terminal fragment. These animals were protected from developing heart failure in response to cardiac stress. Conversely, mice genetically engineered to lose the function of the JP2 fragment in the nuclei developed heart failure at an accelerated rate following cardiac stress.
"Our findings suggest that increasing the level of JP2 fragment or functional peptide in the heart might hold promise as a strategy for treating heart failure," says the senior author. "We have secured a patent for the use of the protein fragment, and intend to investigate gene therapy approaches for delivering it to heart cells in preclinical (animal) models of heart failure."
In addition to its role in heart muscle, JP2 is also important and abundant in other types of muscle (skeletal and smooth). The new findings suggest that JP2 fragmentation may play a role to protect against the adverse effects of stress in all types of muscle.
http://science.sciencemag.org/content/early/2018/11/07/science.aan3303
Heart stress cleaves structural protein into a gene regulator to protect against heart failure
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