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Inhibition of MicroRNA-494 reduces carotid artery atherosclerotic lesion development and increases plaque stability

Publication by: Anouk Wezel, Sabine Welten, Wida Razawy, Max Lagraauw, Margreet de Vries, Eveline Goossens, Martin Boonstra, Jaap Hamming, Ekambar Kandimalla, Johan Kuiper, Paul Quax, Yaël Nossent and Ilze Bot. Annals of Surgery. 2015;262:841-848.

Besides atherosclerotic plaque size, plaque vulnerability is a major determinant of stroke risk. Unstable atherosclerotic lesions in carotid arteries require surgical endarterectomy to reduce the risk of ischemic stroke. Ideally, novel therapeutic strategies to decrease atherosclerotic disease would therefore not only address plaque size, but also plaque stability. MicroRNAs (miRs) are a class of short, noncoding RNAs, approximately 20 nucleotides long, capable of downregulating target gene expression at posttranscriptional level. A single miR has, on average, 200 predicted target genes and as such, MiRs are excellent drug targets for complex diseases, such as atherosclerosis, based on their ability to fine-tune expression of multiple genes. In this study, we thus aimed to identify microRNAs that exert a broad effect on atherosclerotic plaque formation and stability in the carotid artery, which may serve as therapeutic target to inhibit atherosclerosis.

Together with the Vascular Surgery department of the LUMC, we made a selection of 164 genes involved in atherosclerosis. Using www.targetscan.org, we determined which microRNAs potentially regulate expression of these genes. We identified multiple microRNAs from the 14q32 microRNA cluster, which is highly involved in vascular remodeling. In human plaques, collected during carotid endarterectomy surgery, we found that 14q32 microRNA (miR-494) was abundantly expressed in unstable lesions.

"Gene Silencing Oligonucleotides" against miR-494 (GSO-494) or negative control (GSO-control) were injected in hypercholesterolemic mice. Using fluorescently labeled GSOs, we confirmed uptake of GSOs in the plaques, but not elsewhere in the vasculature.

After injection of GSO-494, we observed significant downregulation of miR-494 expression in the carotid arteries and miR-494 target genes were upregulated. Further analyses revealed a 65% decrease in plaque size after GSO-494 treatment. Plaque stability was increased in GSO-494-treated mice, determined by an 80% decrease in necrotic core size and a 50% increase in plaque collagen content. Inhibition of miR-494 also resulted in decreased cholesterol levels and decreased very low-density lipoprotein (VLDL) fractions.

In conclusion, treatment with GSO-494 results in smaller atherosclerotic lesions with increased plaque stability and inhibition of miR-494 may thus decrease the risk of surgical complications or even avert endarterectomy surgery in some cases.

Annals of Surgery, the world's most highly referenced surgery journal, provides the international medical community with information on significant contributions to the advancement of surgical science and practice and has an impact factor of 8.327 (2015).

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