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Aug 11, 2014

Long Noncoding RNA May Lead to New Heart Failure Drug

  • Scientists at the Indiana University School of Medicine say they have found a previously unknown cardiac molecule that could provide a key to treating, and preventing, heart failure. The newly discovered long noncoding RNA molecule provides the heart with a tool to block a protein that orchestrates genetic disruptions when the heart is subjected to stress, such as high blood pressure.

    When the research team, led by Ching-Pin Chang, M.D., Ph.D., associate professor of medicine, restored levels of the lncRNA in mice experiencing heart failure, the progression to heart failure was stopped. The study (“A long noncoding RNA protects the heart from pathological hypertrophy”) research was published in the online edition of Nature.

    RNA's usual role is to carry instructions from the DNA in a cell's nucleus to the machinery in the cell that produces proteins necessary for cell activities. In recent years, scientists have discovered several types of RNA that are not involved in protein coding but act on their own. The role in the heart of lncRNAhas been unknown.

    But the researchers determined that the newly discovered molecule, which they named Myheart (or Mhrt) for myosin heavy-chain-associated RNA transcript, is responsible for controlling the BRG1 protein. In earlier research published in Nature in 2010, Dr. Chang and his colleagues discovered that BRG1 plays a crucial role in the development of the heart in the fetus.

    But as the heart grows and needs to mature into its adult form, BRG1 is no longer needed, so very little of it is produced. That is, until the adult heart is subjected to significant stress such as high blood pressure or damage from a heart attack. Dr. Chang's previous research showed that in those conditions, BRG1 re-emerges and begins altering the heart's genetic activity, leading to heart failure. At the same time, production of Mhrt is suppressed, so BRG1 can latch onto the DNA and alter the genetic material unchecked.

    In the current Nature paper, the researchers reported that in mice with stress-induced high levels of BRG1, they were able to restore Mhrt to normal levels using gene transfer technology. Restoring Mhrt levels blocked BRG1 actions and prevented heart failure, they said.

    “A Mhrt–Brg1 feedback circuit is thus crucial for heart function. Human Mhrt also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy,” wrote the investigators. “Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodeling factors, and establish a new paradigm for lncRNA–chromatin interaction.”

    “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, director of molecular and translational medicine at the Krannert Institute of Cardiology.

    Although the results in mice would suggest testing Myheart against heart failure in humans, it is too large—by molecular standards—to be delivered as a drug, continued Dr. Chang.

    So he and his colleagues now are working to identify smaller portions of the Myheart molecule that are key to its ability to block BRG1. Such a subsection of the Myheart molecule could lead to a compound to test in human trials.


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