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

Mol Ther. 2018 Apr 4;26(4):1040-1055. doi: 10.1016/j.ymthe.2018.01.011. Epub 2018 Jan 31.


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.

Keywords: atherosclerosis; microRNA; molecular medicine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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