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Italian Researchers Detect MicroRNA Signature for Arterial Plaque Instability

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Expression levels of five microRNAs in arterial plaque build up can help predict which individuals are at elevated risk of having these plaques break free, a situation that can lead to stroke and other disease, according to study appearing online last night in the American Heart Association journal Stroke.

Italian researchers found the miRNA signature for plaque instability by comparing expression patterns for 41 miRNAs in Italian patients with atherosclerotic plaque who had or had not had a stroke. The five miRNAs were more highly expressed in plaque samples from stroke victims in both the discovery group and in samples from a validation group that the team tested at another hospital.

"[T]hese findings identify a new potential pharmacological target for plaque stabilization and raise the interesting possibility, which needs to be confirmed by future intervention studies with antisense oligonucleotides, that selective modification in this miRNA signature might provide a novel form of therapy for plaque stabilization in humans," Fiamma Buttitta, a researcher at G. d'Annunzio University, and co-authors wrote.

Atherosclerotic plaques are comprised of cholesterol, calcium, and other molecules circulating in the bloodstream that can become stuck to artery walls. Though some of these plaques remain stable, others break free — a situation that may lead to stroke, heart attack, angina, and other conditions linked to compromised blood movement.

Inflammation and apoptosis seem to contribute to the propensity of these plaques to break free, Buttitta and co-authors noted, but the reasons that such processes are more common in some plaques is poorly understood. For their part, the researchers suspected that they might learn more about plaque instability mechanisms by studying the activity of miRNAs, which can regulate a host of genes.

In an effort to learn more about the miRNA expression coinciding with shifts in plaque stability, the team used Applied Biosystems TaqMan miRNA assays to assess the expression levels of 41 miRNAs in plaque samples from 15 individuals at Chieti Hospital in Italy before doing validation studies involving another 38 patients from a hospital in Ancona, Italy.

The participants were all known to have arterial plaque buildup. Twenty-two of the participants had already had a stroke while 31 had not. The miRNAs selected were suspected of interacting with plaque-related genes.

"We selected these miRNAs according to the involvement of their target genes in the pathophysiology of atherosclerotic plaque growth and instability," the study authors explained.

The researchers detected expression of all 41 miRNAs in plaque samples from the symptomatic and asymptomatic patients enrolled at Chieti Hospital. But five miRNAs — miRNA-100, miRNA-127, miRNA-145, miRNA-133a, and miRNA-133b — had markedly higher expression profiles in the stroke group.

When they tested the expression of the same miRNAs in arterial plaque samples from patients at Ancona Hospital, the team found that four of the five miRNAs had significantly elevated expression levels in the plaque instability group. Expression of the fifth miRNA, miRNA-145, showed a non-significant association with such symptoms.

Moreover, models based on either the four significantly associated miRNAs or on all five miRNAs could accurately predicted 73.5 and 82.4 percent of symptomatic cases, respectively, the researchers reported.

Consistent with their theory that the miRNAs they identified might contribute to plaque characteristics, the team found that they could alter the levels of some proteins involved in plaque-related processes in endothelial cell cultures by adding molecules that mimicked two of the miRNAs.

Along with the possible prognostic value of the miRNA markers, those involved in the study say the findings could help untangle some of the biological processes behind strokes and other related conditions — and point to possible targets for preventing or treating the disease.

"[B]y identifying the specific miRNA signature for stroke now, we are able to use computer algorithms to identify previously unrecognized molecular targets," they wrote. "This approach could ultimately lead to innovative therapeutic approaches in stroke."

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