Effect of Rosuvastatin on MicroRNAs expression in Human Atherosclerotic Plaques: Results from Quasar Study

Background: Statins are the leading therapy for the prevention of ischemic events. MicroRNAs are small non-coding RNAs which act as post-transcriptional gene regulators. Growing evidences support the microRNAs involvement in cardiovascular disease and there are tantalizing hints of the effect of statin on microRNAs. The aim of this study is to investigate whether a short-time treatment with low or high dose of rosuvastatin may affect microRNAs expression in human atherosclerotic plaques. Material and methods: 70 patients with severe stenosis of the internal carotid artery were randomized to receive a 12 week low (10 mg/day) or high (40 mg/day) doses of rosuvastatin before the endarterectomy. Eleven hypercholesterolemic patients without statin therapy were selected as control group. Total RNA was extracted from plaques using Trizol reagent. MiRNome analysis was performed on pooled samples of selected plaques from each group. MicroRNAs validation study and target gene expression were performed on all plaques from the pooled samples by qPCR. Results: MiRNome analysis showed several microRNAs modulated in rosuvastatin groups versus hypercholesterolemic one. Eight microRNAs were found significantly up-regulated in both rosuvastatin groups. At this time, gene expression of MMP-9 and PAI-1, two predicted targets of mir-133a/b and mir-301a, was evaluated in these plaques and we found that they are significantly lower in rosuvastatin groups respect to hypercholesterolemic one. Moreover, mir-133a/b and mir-301a showed a negative correlation with their target gene expression changes. Conclusions: These data showed that rosuvastatin treatment may affect microRNAs expression profile in human atherosclerotic plaques. We also identified MMP-9 and PAI-1 as reliable target genes of up-regulated mir-133a/b and mir-301a. Further studies are required to better elucidate microRNAs involvement in the beneficial effects observed with statin-based lipid lowering therapies.