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Circ Res. 2017 Feb 17;120(4):633-644. doi: 10.1161/CIRCRESAHA.116.309318. Epub 2016 Nov 28.

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions.

Author information

1
From the Department of Medicine (S.M.E., H.J., E.C., Y.L., N.S., C.S., G.K., A.B., A.B., P.E., M.G.D., G.K.H., G.P.-B., L.M.) and Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden (G.K., C.Ö., A.R., T.R., L.P.M., U.H.); Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL (C.Ö.); Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Hamburg-Eppendorf, Germany (T.R.); Department of Vascular and Endovascular Surgery, Technical University Munich and DZHK Partner Site Munich, Germany (H.H.E., J.P., L.M.); Heart Center, Georg-August-University Göttingen, Germany (I.N.S., U.R.); and Division of Cardiovascular Medicine, Stanford University, Palo Alto, CA (N.J.L.).
2
From the Department of Medicine (S.M.E., H.J., E.C., Y.L., N.S., C.S., G.K., A.B., A.B., P.E., M.G.D., G.K.H., G.P.-B., L.M.) and Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden (G.K., C.Ö., A.R., T.R., L.P.M., U.H.); Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL (C.Ö.); Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Hamburg-Eppendorf, Germany (T.R.); Department of Vascular and Endovascular Surgery, Technical University Munich and DZHK Partner Site Munich, Germany (H.H.E., J.P., L.M.); Heart Center, Georg-August-University Göttingen, Germany (I.N.S., U.R.); and Division of Cardiovascular Medicine, Stanford University, Palo Alto, CA (N.J.L.). lars.maegdefessel@tum.de.

Abstract

RATIONALE:

In the search for markers and modulators of vascular disease, microRNAs (miRNAs) have emerged as potent therapeutic targets.

OBJECTIVE:

To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke.

METHODS AND RESULTS:

Using patient material from the BiKE (Biobank of Karolinska Endarterectomies), we profiled miRNA expression in patients with stable versus unstable carotid plaque. A polymerase chain reaction-based miRNA array of plasma, sampled at the carotid lesion site, identified 8 deregulated miRNAs (miR-15b, miR-29c, miR-30c/d, miR-150, miR-191, miR-210, and miR-500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser capture microdissection and in situ hybridization revealed a distinct localization of miR-210 in fibrous caps. We confirmed that miR-210 directly targets the tumor suppressor gene APC (adenomatous polyposis coli), thereby affecting Wnt (Wingless-related integration site) signaling and regulating smooth muscle cell survival, as well as differentiation in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in 2 rodent models of vascular remodeling and plaque rupture. Modulating miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease.

CONCLUSIONS:

An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.

KEYWORDS:

adenomatous polyposis coli; atherosclerosis; carotid stenosis; microRNAs; stroke

PMID:
27895035
DOI:
10.1161/CIRCRESAHA.116.309318
[Indexed for MEDLINE]

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