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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Hong Jin - , Karolinska Institutet (Author)
  • Daniel Y Li - , Technical University of Munich (Author)
  • Ekaterina Chernogubova - , Karolinska Institutet (Author)
  • Changyan Sun - , Karolinska Institutet (Author)
  • Albert Busch - , Technical University of Munich, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Suzanne M Eken - , Karolinska Institutet (Author)
  • Peter Saliba-Gustafsson - , Karolinska Institutet (Author)
  • Hanna Winter - , Karolinska Institutet (Author)
  • Greg Winski - , Karolinska Institutet (Author)
  • Uwe Raaz - , Medical University of Graz (Author)
  • Isabel N Schellinger - , Medical University of Graz (Author)
  • Nancy Simon - , Karolinska Institutet (Author)
  • Renate Hegenloh - , Technical University of Munich (Author)
  • Ljubica Perisic Matic - , Karolinska Institutet (Author)
  • Maja Jagodic - , Karolinska Institutet (Author)
  • Ewa Ehrenborg - , Karolinska Institutet (Author)
  • Jaroslav Pelisek - , Technical University of Munich (Author)
  • Hans-Henning Eckstein - , Technical University of Munich (Author)
  • Ulf Hedin - , Karolinska Institutet (Author)
  • Alexandra Backlund - , Karolinska Institutet (Author)
  • Lars Maegdefessel - , Technical University of Munich (Author)

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.

Details

Original languageEnglish
Pages (from-to)1040-1055
Number of pages16
JournalMolecular Therapy
Volume26
Issue number4
Publication statusPublished - 4 Apr 2018
Peer-reviewedYes
Externally publishedYes

External IDs

PubMedCentral PMC6080193
Scopus 85042628745

Keywords

Keywords

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