In heart failure, the heart is unable to pump blood effectively throughout the body. One key factor in the development of this condition is calcium dysregulation. A newly discovered molecule that may be able to address this issue could become the next therapeutic target for this heart condition.

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Will a newly discovered molecule become the next therapeutic target for heart failure?

The heart can contract, relax, and pump blood through the veins effectively, partly due to a process called “calcium cycling.” This process allows calcium to circulate in and out of cells.

This cycle is sometimes impaired by a person’s age, which can also affect the rate or potency with which the heart muscle pumps out blood.

Calcium dysregulation may therefore lead to the development of heart failure.

So far, researchers have focused on developing therapies targeting a molecule known as SERCA, whose role is to transport calcium ions, ensuring the relaxation of the heart muscle.

In heart failure, SERCA does not function properly, which has led some scientists to look into the possibilities of developing a gene therapy that would increase SERCA expression.

Now, however, specialists from the University of Texas Southwestern in Dallas, and from Loyola University Chicago in Illinois, have discovered a micropeptide, which they named “dwarf open reading frame” (DWORF). The scientists believe that DWORF could pave the way to better treatments for heart failure.

“Our lab recently discovered a micropeptide called [DWORF], which binds directly to SERCA and enhances its activity,” explains the lead author of this new study, Catherine Makarewich.

In this study, we explored the therapeutic potential of high levels of DWORF, as a way to increase SERCA activity and improve heart contractility in heart failure.”

Catherine Makarewich

Makarewich and team first found that DWORF displaces a molecule called phospholamban (PLN), which inhibits SERCA activity.

This suggested that scientists might be able to use DWORF to help boost SERCA activity, thus allowing the heart to regain its ability to contract and relax effectively.

In the current study, whose findings appear in the journal eLife, the researchers worked with mice that they genetically engineered to express higher levels of DWORF, higher levels of PLN, or higher levels of both DWORF and PLN in the heart.

By comparing genetically engineered rodents with normal ones, the scientists noticed that the mice with higher DWORF levels had better calcium cycling than regular mice.

At the same time, the mice engineered to express higher PLN levels had poorer calcium cycling compared with the controls. Finally, in the mice with high levels of both molecules, DWORF prevented the impact of PLN.

In order to consolidate these findings, the researchers also assessed the effects of DWORF in a mouse model of dilated cardiomyopathy, in which the heart becomes enlarged and unable to pump blood efficiently.

Regular mice with dilated cardiomyopathy had poor function of the left heart ventricle, the part of the heart that pumps oxygenated blood towards the body.

Mice with dilated cardiomyopathy that were also engineered to have higher levels of DWORF, however, showed better function of the left heart ventricle.

Conversely, rodents with the same heart problem but with no DWORF at all displayed even poorer left ventricle function than the controls.

Makarewich and team also noted that mice with high DWORF levels did not show some of the usual physiological signs of cardiomyopathy, such as enlarged heart chambers, thinning of the chamber walls, and a higher volume of heart muscle cells.

Also, the mice with high DWORF levels did not develop a buildup of scar tissue in the heart, which is another characteristic of cardiomyopathy.

“Previous attempts to restore SERCA to protect against heart failure have been unsuccessful because they have focused on increasing levels of SERCA itself,” notes the study’s senior author, Eric Olson.

Based on the current findings, however, he thinks the team may have identified a more viable therapeutic target in DWORF.

“We believe that increasing levels of DWORF instead may be more feasible and that the small size of the DWORF molecule could make it an attractive candidate for a gene therapy drug for heart failure,” Olson adds.