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

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.

• Authors: Suzanne M Eken, Hong Jin, Ekaterina Chernogubova, Yuhuang Li, Nancy Simon, Changyan Sun, Greg Korzunowicz, Albert Busch, Alexandra Bäcklund, Cecilia Österholm, Anton Razuvaev, Thomas Renné, Hans Henning Eckstein, Jaroslav Pelisek, Per Eriksson, María González Díez, Ljubica Perisic Matic, Isabel N Schellinger, Uwe Raaz, Nicholas J Leeper, Göran K Hansson, Gabrielle Paulsson-Berne, Ulf Hedin, Lars Maegdefessel
• Journal: Circulation research (Circ Res) Vol. 120 Issue 4 Pg. 633-644 (Feb 17 2017) ISSN: 1524-4571 [Electronic] United States
• PMID: 27895035 (Publication Type: Journal Article)
• Copyright: © 2016 American Heart Association, Inc.

Chemical References

• MIRN210 microRNA, human
• MicroRNAs

Topics

• Animals
• Atherosclerosis (metabolism, pathology, therapy)
• Carotid Stenosis (metabolism, pathology, therapy)
• Cells, Cultured
• Cohort Studies
• Endothelial Cells (metabolism, pathology)
• Humans
• Laser Capture Microdissection (methods)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (administration & dosage, analysis, biosynthesis)
• Plaque, Atherosclerotic (metabolism, pathology, therapy)
• Rats
• Rats, Sprague-Dawley
• Stroke (metabolism, pathology, prevention & control)