MicroRNA-221 sponge therapy attenuates neointimal hyperplasia and improves blood flows in vein grafts

Int J Cardiol. 2016 Apr 1:208:79-86. doi: 10.1016/j.ijcard.2016.01.006. Epub 2016 Jan 12.

Abstract

Background: Vein graft failure due to neointimal hyperplasia remains an important and unresolved problem of cardiovascular surgery. MicroRNA-221 (miR-221) has been shown to play a major role in regulating vascular smooth muscle cell (VSMC) proliferation and phenotype transformation. Thus, the purpose of this study is to determine whether adenovirus mediated miR-221 sponge gene therapy could inhibit vein graft neointimal hyperplasia.

Methods: Adenovirus encoding miR-221 sponge (Ad-miR-221-SP) was used to inhibit VSMC proliferation in vitro and neointimal formation in vivo. Expression of miRNA-221 was evaluated in cultured VSMC and in rat vein graft models following transduction with Ad-miR-221-SP, Ad-Control-SP (without miR-221 antisense binding sites), or Ad-GFP (control). To accelerate the transfer of miR-221 sponge gene to the vein grafts, 20% poloxamer F-127 gel was used to extend virus contact time and 0.25% trypsin to increase virus penetration.

Results: miR-221 sponges can significantly decrease the expression of miR-221 and proliferation in cultured VSMC. Cellular proliferation rates were significantly reduced in miR-221 sponge treated grafts as compared with controls at 6 weeks after bypass surgery (19.8% versus 43.6%, P=0.0028). miR-221 sponge gene transfer reduced the neointimal area (210.75 ± 24.13 versus 67.01 ± 12.02, P<0.0001), neointimal thickness (171.86 ± 27.87 versus 64.13 ± 16.23, P<0.0001) and neointima/media ratio (0.74 ± 0.21 versus 1.95 ± 0.25, P<0.0001) in vein grafts versus controls. miR-21 sponge treatment was also improved hemodynamics in vein grafts. We have further identified that p27 (Kip1) is a potential target gene of miR-221 in vein grafts.

Conclusion: miR-221 sponge therapy can significantly reduce miR-221 activity and inhibit neointimal hyperplasia in vein grafts. Locally adventitial delivery of adenoviruses mediated miRNA sponges may be promising gene therapies to prevent vein graft failure.

Keywords: Gene therapy; MicroRNA; Neointimal formation; Sponges; Vein graft disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Blood Flow Velocity / physiology*
  • Cells, Cultured
  • Genetic Therapy / methods*
  • Hyperplasia / genetics
  • Hyperplasia / physiopathology
  • Hyperplasia / therapy
  • Jugular Veins / physiology
  • Jugular Veins / transplantation*
  • Male
  • MicroRNAs / administration & dosage*
  • MicroRNAs / genetics
  • Muscle, Smooth, Vascular / physiology
  • Muscle, Smooth, Vascular / transplantation
  • Neointima / genetics
  • Neointima / physiopathology
  • Neointima / therapy*
  • Rats
  • Rats, Sprague-Dawley
  • Vascular Grafting / methods*

Substances

  • MIRN221 microRNA, rat
  • MicroRNAs