Newly Discovered Large Molecule Could be Key to Treating Heart Failure

from Bioresearch Online by C. Rajan, contributing writer

Researchers at the Indiana University School of Medicine have just discovered a molecule which allows the heart to block a protein that creates genetic disruptions when the heart is subjected to stressful conditions, such as high blood pressure. This previously unknown molecule could help in treating and preventing heart failure.

The newly discovered molecule is a long non-coding RNA (lncRNA), which the researchers have named Myheart—for myosin heavy-chain-associated RNA transcript. Until now, the role of long non-coding RNA in the heart has been unknown.

Dr. Ching-Pin Chang, M.D., Ph.D., associate professor of medicine at the Indiana University School of Medicine, led the research team, which found that insufficient levels of this new molecule, Myheart, could lead to heart failure. When they restored levels of Myheart in mice experiencing heart failure, the progression to heart failure ceased.

Dr. Chang’s team determined that Myheart’s beneficial effect in stopping heart failure was due to its ability to control an important protein called BRG1 (pronounced “berg-1”). BRG1 is a transcription co-regulator which is critical for the proper development of the embryo and fetus. In fact, in 2010, Dr. Chang himself and his team were the ones to the role BRG1 plays in the development of the heart in the fetus.

BRG1 is not essential in adults and very little of it is produced under normal conditions. However, when the adult heart is subjected to stress such as high blood pressure, BRG1 is produced again and begins altering the heart’s genetic activity, which leads to heart failure. Under these conditions, production of Myheart is also suppressed, so that BRG1 is able to alter the genetic material freely.

The researchers reported that they restored Myheart to normal levels using gene transfer technology in mice with stress-induced high levels of BRG1, and that this restoration of Myheart blocked BRG1 actions and prevented 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 Dr. Chang.

The promising results with Myheart in mice cannot be translated to testing in humans at this point, as the molecule is too large to be used as a drug. Dr. Chang and his colleagues are now working to identify the particular subsection of the Myheart molecule which is necessary to block BRG1, so that they can have a smaller molecule to test in human trials.

There is already interest in developing a small-molecule inhibitor or drug that can successfully block BRG1 function in leukemia, as BRG1 has also been implicated in tumor progression of leukemia. It is possible that drugs that block BRG1 may lead to treatments for both cardiac conditions and leukemia.

Dr. Chang’s study was recently published in the online edition of the journal Nature.