Unique MicroRNA Signature Present in Unstable Carotid Plaque

Megan Brooks

August 05, 2011

August 5, 2011 — A unique micro (mi)RNA signature characterizes atherosclerotic plaque that is prone to rupture and cause stroke, Italian researchers report.

They found that carotid atherosclerotic plaque from stroke patients expressed higher levels of 5 miRNAs than carotid atherosclerotic plaque from asymptomatic patients: miRNA-100, miRNA-127, miRNA-145, miRNA-133a, and miRNA-133b.

The findings point to "a potential role for miRNAs in the homeostasis of atherosclerotic plaques in humans and identify a new potential pharmacological target for plaque stabilization," Francesco Cipollone, MD, from University in Chieti G. D'Annunzio School of Medicine, in Italy, and colleagues write.

The findings were published online August 4 in Stroke.

Unique MicroRNA Signature

The researchers collected atherosclerotic plaques from patients who underwent carotid endarterectomy for extracranial high-grade internal carotid artery stenosis at 2 different Italian hospitals — one in Chieti and one in Ancona. They subdivided the plaques into symptomatic (n = 22) and asymptomatic (n = 31) groups, according to the presence or absence of clinically related stroke.

In the Chieti group, a large-scale analysis of 41 miRNAs revealed significant differences in the expression of 5 miRNAs (miRNA-100, 127, 145, 133a, and 133b) between symptomatic and asymptomatic plaques. All 5 were overexpressed in plaques from symptomatic patients.

"Remarkably," note the researchers, 4 of the 5 miRNAs (miRNA-100, 127, 133a, and 133b) were also significantly overexpressed in plaques from symptomatic patients in the Ancona group. The fifth miRNA (miRNA-145) showed a nonsignificant trend toward an association with symptomatic plaques.

"We believe the observation that 1 specific miRNA signature characterizes plaques prone to rupture in 2 different groups of patients recruited in 2 different hospitals by 2 totally independent surgical teams is very important, because it rules out the possibility that results were influenced by variables such as diagnostic procedures, specific surgical techniques, and concomitant medical therapies," the study team writes.

In a predictive model of clinical outcome, the 4-miRNA signature (not including miRNA-145) correctly predicted 73.5% of stroke cases, and the 5-miRNA signature correctly predicted 82.4% of stroke cases, they report.

They say it is notable that the expression patterns of the 5 miRNAs were "always comparable to each other; therefore, plaques that were highly positive in 1 of the 4 miRNAs were also highly positive in the remaining 3 miRNAs, and no plaque was found to be positive in only 1 of these miRNAs."

According to the researchers, this observation is "of interest, because it seems to suggest that miRNA-100, miRNA-127, miRNA-133a, and miRNA-133b are concomitantly expressed in the same cells in the plaques and that complex regulatory mechanism(s) intimately linking these 4 miRNAs may exist."

It is also noteworthy, the researchers say, that the expression of this specific miRNA signature in vulnerable plaques was not associated with a higher presence of 1 specific risk factor, such as diabetes, hypertension, dyslipidemia, or smoking.

This "clearly supports the view that local factors or genetic traits per se, rather than metabolic factors, are responsible for miRNA regulation in cells infiltrating vulnerable plaques," they write.

Four of the miRNAs are "deeply involved" in the modulation of inflammation and other processes critical to plaque evolution.

The researchers report that, taken together, these findings "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."

The study was supported by academic research funds. The authors have disclosed no relevant financial relationships.

Stroke. Published online August 4, 2011. Abstract

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