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Small Molecule, Big Threat

14 November 2006 (All day)
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PNAS

Big, bad heart.
A normal mouse heart (top) becomes enlarged when a particular miRNA is expressed.

A tiny sliver of RNA can destroy an animal's heart, according to research published online this week in Proceedings of the National Academy of Sciences. The finding boosts evidence that such fragments--known as microRNAs (miRNAs)--play important roles in health and disease.

Hundreds of miRNAs have been identified in plants and animals. Despite their tiny size--less than 0.2% the length of the average gene--miRNAs exert a powerful amount of control on gene expression (ScienceNOW, 19 January 2005). Scientists have found that miRNAs regulate early development, for example, and may play a role in cancer progression. But while more and more researchers are exploring the link between miRNAs and cancer, the molecules haven't been publicly tied to other diseases.

On a lark, molecular biologist Eric Olson of the University of Texas Southwestern Medical Center in Dallas set out to learn whether any miRNAs were involved in stressed-out hearts. First, Olson and colleagues looked for expression of miRNAs in heart tissue from mice with experimentally induced heart failure. The team identified 186 different miRNAs, 11 of which were more highly expressed in the unhealthy mice than in normal mice, and five of which were expressed at lower levels than in normal mice. Five of the miRNAs with higher expression were also found in unusually high quantities in heart tissue collected from people with heart failure.

To see whether some of these miRNAs could cause heart failure--as opposed to simply reacting to it--Olson's team overexpressed three of the miRNAs, separately, in mice. "I was skeptical," Olson recalls. Yet one did indeed leave mice with severely abnormal hearts when overexpressed at levels 25 times those found in normal animals. What's more, the heart defects resembled defects seen in humans with heart failure, in which cardiac muscle cells stretch in size, says Olson. But it's not clear how this is happening; the researchers haven't yet determined which gene or genes the miRNA targets.

Michael McManus, an RNA biologist at the University of California, San Francisco, predicts that the work may prompt scientists in other disease areas to examine whether miRNAs have a role there. Victor Ambros, a geneticist at Dartmouth Medical School in Hanover, New Hampshire, notes that this is one of the first studies he's seen that hunts for links between miRNAs and tissue trauma. Olson's team plans to continue down this path--in particular, he says, he wonders whether genetically erasing the miRNA that prompted heart failure in mice can prevent it.

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