Inflammatory Responses Involving Tumor Necrosis Factor Receptor-Associated Factor 6 Contribute to In-Stent Lesion Formation in a Stent Implantation Model of Rabbit Carotid Artery

J Vasc Surg. 2006 Mar;43(3):592-600. doi: 10.1016/j.jvs.2005.11.010.

Abstract

Objective: Inflammatory responses are considered to represent a unique property after stent implantation, and we previously demonstrated that inflammatory signaling involving tumor necrosis factor receptor-associated factor 6 (TRAF6) contributes to neointimal formation in a balloon injury model of rabbit carotid artery. The purpose of this study was to examine the role of TRAF6 in in-stent lesion formation after stent implantation in the rabbit carotid artery.

Methods: Rabbit carotid arteries were injured with a 2F Fogarty catheter, and 28 days later, the same arteries were implanted with a 3-mm-diameter Palmaz-Schatz stent. A dominant negative (DN) form of TRAF6 (pME-FLAG-T6deltaRZ5) was then transferred using a plasmid-based electroporation method. Its effects were evaluated compared with the findings in arteries treated with control plasmid (pME-FLAG).

Results: Immunostaining with anti-FLAG tag antibody showed that an expression plasmid vector containing the DN-TRAF6 sequence was successfully transferred to the arterial intima and media. Morphometric analyses revealed that the increase of intimal area in in-stent lesions was significantly inhibited by DN-TRAF6 14 days after stent implantation (DN-TRAF6 group, 3.01 +/- 0.25 x 10(5) microm2 vs control group, 4.25 +/- 0.23 x 10(5) microm2, P < .01), and the cell density was increased compared with that in the control group. In the DN-TRAF6 plasmid-treated vessels, cell replication was prevented in both the intima and media, and fewer leukocytes adhered to the luminal surface. Moreover, DN-TRAF6 suppressed macrophage infiltration, activation of proteases, and proteoglycan accumulation in the in-stent intima.

Conclusions: These findings suggest that TRAF6 plays an important role in cell replication, inflammatory cell infiltration, protease activity, and extracellular matrix accumulation that contributes to in-stent lesion development.

MeSH terms

  • Animals
  • Carotid Arteries / pathology*
  • Cell Count
  • Electroporation
  • Male
  • Microscopy, Electron, Scanning
  • Microscopy, Electron, Transmission
  • Rabbits
  • Stents / adverse effects*
  • TNF Receptor-Associated Factor 6 / physiology*
  • Tunica Intima / pathology
  • Tunica Media / pathology

Substances

  • TNF Receptor-Associated Factor 6