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Dec 19, 2013

Preventing Atherosclerosis by Targeting microRNA

  • Scientists from Emory University and Georgia Tech say they have developed a potential treatment for atherosclerosis that targets a master controller of the process. Surprisingly to the researchers, the master controller comes from a source they had thought was leftover garbage: a microRNA molecule.

    The study (“The atypical mechanosensitive microRNA-712 derived from preribosomal RNA induces endothelial inflammation and atherosclerosis”) appears in Nature Communications.

    The treatment works by stopping the inflammatory effects of disturbed blood flow on cells that line blood vessels. In animal models of atherosclerosis, a drug that blocks the microRNA can stop arteries from becoming blocked, despite the ongoing stress of high-fat diet. The microRNA appears to function similarly in human cells.

    “We…show that miR-712 is derived from an unexpected source, preribosomal RNA, in an exoribonuclease-dependent but DiGeorge syndrome critical region 8-independent manner, suggesting that it is an atypical miRNA,” write the investigators. “Mechanistically, d-flow-induced miR-712 downregulates tissue inhibitor of metalloproteinase 3 (TIMP3) expression, which in turn activates the downstream matrix metalloproteinases and a disintegrin and metalloproteases, and stimulates pro-atherogenic responses, endothelial inflammation, and permeability. Furthermore, silencing miR-712 by anti-miR-712 rescues TIMP3 expression and prevents atherosclerosis in murine models of atherosclerosis.”

    According to senior author Hanjoong Jo, Ph.D. “Healthy [blood] flow tunes down the production of bad actors like this microRNA. Targeting it could form the basis for a therapeutic approach that could be translated with relative ease compared to other drugs.”

    Dr. Jo and his colleagues have developed an animal model where it is possible to drive the development of atherosclerosis quickly and selectively, by partially restricting blood flow in a mouse's carotid artery. To accelerate the process, the mice also have a deficiency in ApoE, important for removing lipids and cholesterol from the blood, and are fed a high-fat diet. The model allows researchers to compare molecules that are activated in endothelial cells, which line blood vessels, on the disturbed side versus the undisturbed side in the same animal.

    The research team focused on microRNAs, short snippets of RNA that can inhibit the activity of many genes at once. MicroRNAs were recently discovered to be able to travel from cell to cell, and thus could orchestrate processes such as atherosclerosis. Out of all the microRNAs the researchers examined, one in particular, called miR-712, was the microRNA most strongly induced by disturbed blood flow in the atherosclerosis model system.

    In response to disturbed or unhealthy blood flow, endothelial cells produce miR-712, the researchers found. miR-712 in turn inhibits a gene called TIMP3, which under healthy flow conditions restrains inflammation in endothelial cells.

    The researchers were surprised to find that miR-712 comes from leftovers remaining from a long RNA that is used to form ribosomes. Ribosomes are ubiquitous and perform the basic housekeeping function of protein assembly.

    By using locked nucleic acids technology, Dr. Jo and his colleagues tested the effects of blocking miR-712 in the body. When given to mice in the rapid atherosclerosis model, the anti-miR-712 drug inhibited the development of arterial blockages. Without the drug, plaques blocked an average of 80 percent of the disturbed carotid artery, but the drug cut that in half. The drug worked similarly in another model of atherosclerosis where animals develop disease more slowly.

    Dr. Jo says his team is devising ways using nanotechnologies to deliver anti-miR-712 drugs to the heart or to endothelial cells specifically to achieve efficient therapeutic effect with minimum side effects.



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