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Therapeutic silencing of microRNA-33 inhibits the progression of atherosclerosis in Ldlr-/- mice--brief report

Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1973-7. doi: 10.1161/ATVBAHA.113.301732. Epub 2013 May 23.

Abstract

Objective: To study the efficacy of anti-miRNA-33 therapy on the progression of atherosclerosis.

Approach and results: Ldlr(-/-) mice were injected subcutaneously with PBS, control, or anti-miR-33 oligonucleotides weekly and fed a Western diet for 12 weeks. At the end of treatment, the expression of miR-33 target genes was increased in the liver and aorta, demonstrating effective inhibition of miR-33 function. Interestingly, plasma high-density lipoprotein (HDL)-cholesterol was significantly increased in anti-miR-33-treated mice but only when they were fed a chow diet. However, HDL isolated from anti-miR-33-treated mice showed an increase cholesterol efflux capacity compared with HDL isolated from nontargeting oligonucleotide-treated mice. Analysis of atherosclerosis revealed a significant reduction of plaque size and macrophage content in mice receiving anti-miR-33. In contrast, no differences in collagen content and necrotic areas were observed among the 3 groups.

Conclusions: Long-term anti-miR-33 therapy significantly reduces the progression of atherosclerosis and improves HDL functionality. The antiatherogenic effect is independent of plasma HDL-cholesterol levels.

Keywords: ABCA1 protein; atherosclerosis; cholesterol, HDL; macrophages; miR-33.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Feed
  • Animals
  • Atherosclerosis / genetics*
  • Atherosclerosis / pathology
  • Atherosclerosis / therapy*
  • Cholesterol, HDL / blood
  • Disease Progression
  • Gene Silencing
  • Genetic Therapy / methods*
  • Injections, Subcutaneous
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Oligonucleotides / genetics
  • Oligonucleotides / pharmacology
  • Receptors, LDL / genetics*

Substances

  • Cholesterol, HDL
  • MicroRNAs
  • Mirn33 microRNA, mouse
  • Oligonucleotides
  • Receptors, LDL