A team of scientists at the University of Texas Southwestern Medical Center, Dallas have discovered a new molecule that could be the cure for heart disease caused by calcium dysregulation.
Using mice they found the new molecule not only combated this problem but also had other unexpected benefits for mice with dilated cardiomyopathy.
What is Calcium Dysregulation?
In a healthy heart, the muscles of the organ can contract, relax and, therefore, pump blood around the body. This process, in part, relies on a process called "calcium cycling".
This cell function is vital to the healthy workings of your heart and controls calcium circulation in and out of heart cells. If this process is perturbed for any reason it can lead to the development of heart failure.
"Calcium cycling" is normally the role of another molecule called SERCA whose role is to ferry calcium ions through cell membranes. If this molecule isn't doing its job properly it disrupts the movement of calcium ions and impairs heart function.
Up to now, research has focussed on developing therapies to target the malfunctioning SERCA molecules to treat the disorder.
What did the team find?
The researchers at the University of Texas Southwestern in Dallas, and from Loyola University Chicago in Illinois have found a micro peptide that could be the solution to this issue. This new molecule has been dubbed "dwarf open reading frame" (DWORF) by the team.
Research team member, Catherine Makarewich. explains that "our lab recently discovered a micro-peptide called [DWORF], which binds directly to SERCA and enhances its activity,"
They found that DWORF displaces another molecule called phospholamban (PLN) that inhibits SERCA activity.
Their study has recently been published in eLife which describes how they used to work with genetically modified mice. These mice were engineered to express high levels of DWORF, higher levels of PLN, or higher levels of both DWORF and PLN in the heart.
They noticed that those mice with higher DWORF levels showed marked improvement in calcium cycling compared to non-modified controls. Conversely, those mice with higher PLN expression showed, unsurprisingly, poorer calcium cycling (compared to control mice).
For the final group (high DWORF and PLN) the higher levels of PLN were mitigated by the presence of DWORF.
They also tested DWORF on mice with dilated cardiomyopathy. This is a condition where the heart becomes overly enlarged and ineffective at pumping blood.
When engineered to express DWORF they found a noticeable improvement in left ventricle function as well as other improvements to expected physiology related to the disorder (enlarged heart chambers, thin chamber walls etc).
What's the significance of this study?
If their findings are correct, DWORF could provide a new gene therapy that will significantly increase SERCA expression in patients.
"Previous attempts to restore SERCA to protect against heart failure have been unsuccessful because they have focused on increasing levels of SERCA itself," said Eric Olsun, the study's senior author.
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.
The original study is published in the journal eLife Sciences.