Inflammatory signaling pathway containing TRAF6 contributes to neointimal formation via diverse mechanisms.
OBJECTIVE
The purpose of this study was to investigate the contribution of inflammatory signaling containing tumor necrosis factor receptor-associated factor 6 (TRAF6) to neointimal formation in a balloon injury model of rabbit carotid artery.


METHODS
Male Japanese white rabbits fed a normal diet were used. We transferred the dominant negative (DN) form of TRAF6 to a rabbit carotid artery that was subjected to balloon injury by in vivo electroporation method, and then evaluated its effect on intimal lesion formation after balloon injury.


RESULTS
An expression plasmid vector containing the TRAF6 DN sequence was successfully transferred to arterial wall cells, and its inhibitory effect on inflammatory signaling was confirmed by the marked suppression of nuclear factor-kappaB (NFkappaB) activity after injury. Morphometric analyses revealed significant inhibition of intimal lesion formation at 7 days after injury. Cell replication and accumulation of macrophages in the media were significantly decreased, and apoptosis was enhanced on day 2. Cell migration to the intima was suppressed on day 4. Extracellular signal-regulated kinase1/2 (ERK1/2) activity at 2 h after injury was also down-regulated. Interestingly, intimal cell replication was significantly blocked when TRAF6 DN was transfected at 7 days after injury.


CONCLUSIONS
TRAF6 plays important roles in cell replication and migration, besides promotion of inflammatory cell infiltration and suppression of apoptosis.
Miyahara
Takuya
T
Department of Vascular Regeneration, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan.
Koyama
Hiroyuki
H
Miyata
Tetsuro
T
Shigematsu
Hiroshi
H
Inoue
Jun-Ichiro
J
Takato
Tsuyoshi
T
Nagawa
Hirokazu
H
D000818:Animals; D001161:Arteriosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002339:Carotid Arteries; D002404:Catheterization; D002465:Cell Movement; D004247:DNA / Q000008:administration & dosage; D018274:Electroporation; D005799:Genes, Dominant; D008264:Macrophages / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D023421:Models, Animal; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism; D009389:Neovascularization, Pathologic; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017539:Tunica Intima / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D004247:DNA; D020928:Mitogen-Activated Protein Kinases