When human fetuses are in the early phase of development, a protein molecule known as BRG1 plays an important role by turning genes related to heart muscle on and off. Soon, however, production of the protein drops significantly because it is no longer needed.
What researchers have learned in recent years, however, is that stress can spur a return of BRG1 production, which can cause heart muscle to enlarge and thicken and in turn cause heart failure.
In an article just published online by the journal Nature, researchers at Indiana University report finding a molecule that can block reactivation of BRG1 and potentially treat and even prevent heart failure.
The heretofore unknown molecule is what molecular biologists have dubbed a noncoding RNA. Unlike other types of RNA, noncoding RNAs play no direct role in transcribing the genetic information in DNA into the chains of amino acids know as protein molecules.
The molecule has been dubbed myosin heavy-chain-associated RNA transcript — Myheart for short — by its discoverers, Ching-Pin Chang of Indiana University and his collaborators. A report Nature published in 2010, while Chang was still at the Stanford University School of Medicine, outlined the role of BRG1 in fetal heart development and the onset of heart failure in adults.
Chang, now director of molecular and translational medicine at the IU Krannert Institute of Cardiology, and his colleague found that the rise in BRG1 in adult hearts in response to stress such as high blood pressure or heart attacks doesn’t just cause enlargement and thickening of heart muscle. It also interferes with the production of the Myheart molecule.
In the absence of Myheart, BRG1 is free to attach itself to DNA and cause the genetic changes that produce the cardiac muscle damage associated with heart failure. “I think of Myheart as a molecular crowbar that pries BRG1 off the genomic DNA and prevents it from manipulating genetic activity,” said Chang.
Chang and his colleagues used a molecular engineering technique known as gene transfer to restore Myheart to normal levels in lab mice with high levels of BRG1 as a result of cardiac stress. Restoring their Myheart levels prevented the mice from developing heart failure.
Since the full Myheart molecule is so large, however, it is an unlikely candidate to be turned into a drug that could treat or prevent heart failure in humans, according to Chang. Instead, his team is now looking for a smaller section of Myheart that will still block the action of BRG1.
If they are successful, that smaller molecule could be turned into a compound that would be ready for human clinical testing.
In addition to the IU researchers, Chang had collaborators at the Stanford School of Medicine; the Albert Einstein College of Medicine, in New York; and the Sanford/Burnham Medical Research Institute, in Orlando.