A novel antioxidant 3,7-dihydroxy-isoflav-3-ene (DHIF) inhibits neointimal hyperplasia after vessel injury attenuating reactive oxygen species and nuclear factor-κB signaling

Peter Kanellakis, Giovanna Pomilio, Catherine Walker, Alan J Husband, Jiu Li Huang, Paul John Nestel, Alex Agrotis, Alex Bobik

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15 Citations (Scopus)

Abstract

Reactive oxygen species (ROS) contribute to neointimal smooth muscle proliferation by yet to be defined mechanisms. We examined the effects of a novel isoflavone 3,7-dihydroxy-isoflav-3-ene (DHIF) on development of neointimal lesions in relation to ROS elevations and cell signaling in injured arteries. Carotid arteries of rabbits treated with vehicle or DHIF were injured with a balloon catheter and effects on proliferation, apoptosis, vessel structure, ROS, NF-κB activation, cyclooxygenase and gene expression examined. Seven days after injury proliferating neointimal cells were reduced by 35% (P < 0.05) whilst medial cell proliferation was attenuated by 16% (P < 0.05). ROS levels were elevated fourfold in injured arteries of vehicle-treated rabbits. Treatment with DHIF prevented this elevation (P < 0.05). Also, NF-κB was activated in neointimal cells from vehicle-treated rabbits, demonstrated by nuclear accumulation of NF-κB-p65. DHIF not only attenuated its nuclear accumulation but also suppressed NF-κB-p65 expression in neointimal cells. This was accompanied by a doubling of apoptotic cell numbers (P < 0.05). Expression of cyclooxygenases Cox-1 and Cox-2 were also attenuated, by 74% and 50%, respectively (P < 0.05), as was MCP-1. The antiproliferative effects of DHIF persisted at 14 days, and 28 days after injury neointima growth was attenuated by 50% (P < 0.05). Thus, ROS stimulates neointima growth via mechanisms involving NF-κB activation, cyclooxygenases and MCP-1. DHIF's ability to attenuate NF-κB activation suggests that it may not only be useful in preventing restenosis but also in attenuating atherosclerosis.

Original languageEnglish
Pages (from-to)66-72
Number of pages7
JournalAtherosclerosis
Volume204
Issue number1
DOIs
Publication statusPublished - May 2009
Externally publishedYes

Keywords

  • Cyclooxygenase
  • Neointima
  • NF-κB
  • Superoxide
  • Vessel injury

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