Local Delivery of miR-21 Stabilizes Fibrous Caps in Vulnerable Atherosclerotic Lesions.

Abstract

miRNAs are potential regulators of carotid artery stenosis and concordant vulnerable atherosclerotic plaques. Hence, we analyzed miRNA expression in laser captured micro-dissected fibrous caps of either ruptured or stable plaques (n = 10 each), discovering that miR-21 was significantly downregulated in unstable lesions. To functionally evaluate miR-21 in plaque vulnerability, miR-21 and miR-21/apolipoprotein-E double-deficient mice (Apoe-/-miR-21-/-) were assessed. miR-21-/- mice lacked sufficient smooth muscle cell proliferation in response to carotid ligation injury. When exposing Apoe-/-miR-21-/- mice to an inducible plaque rupture model, they presented with more atherothrombotic events (93%) compared with miR-21+/+Apoe-/- mice (57%). We discovered that smooth muscle cell fate in experimentally induced advanced lesions is steered via a REST-miR-21-REST feedback signaling pathway. Furthermore, Apoe-/-miR-21-/- mice presented with more pronounced atherosclerotic lesions, greater foam cell formation, and substantially higher levels of arterial macrophage infiltration. Local delivery of a miR-21 mimic using ultrasound-targeted microbubbles into carotid plaques rescued the vulnerable plaque rupture phenotype. In the present study, we identify miR-21 as a key modulator of pathologic processes in advanced atherosclerosis. Targeted, lesion site-specific overexpression of miR-21 can stabilize vulnerable plaques.

• Authors: Hong Jin, Daniel Y Li, Ekaterina Chernogubova, Changyan Sun, Albert Busch, Suzanne M Eken, Peter Saliba-Gustafsson, Hanna Winter, Greg Winski, Uwe Raaz, Isabel N Schellinger, Nancy Simon, Renate Hegenloh, Ljubica Perisic Matic, Maja Jagodic, Ewa Ehrenborg, Jaroslav Pelisek, Hans-Henning Eckstein, Ulf Hedin, Alexandra Backlund, Lars Maegdefessel
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 26 Issue 4 Pg. 1040-1055 (04 04 2018) ISSN: 1525-0024 [Electronic] United States
• PMID: 29503197 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Lipoproteins, LDL
• MIRN-21 microRNA, mouse
• MicroRNAs
• oxidized low density lipoprotein

Topics

• Animals
• Apoptosis (genetics)
• Atherosclerosis (genetics, pathology)
• Carotid Artery Diseases (genetics, pathology)
• Disease Models, Animal
• Fibrosis
• Gene Expression Profiling
• Gene Transfer Techniques
• Genotype
• Humans
• Immunohistochemistry
• Lipoproteins, LDL (metabolism)
• Macrophages (metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• MicroRNAs (administration & dosage, genetics)
• Myocytes, Smooth Muscle (metabolism, pathology)
• Plaque, Atherosclerotic (genetics, pathology)