Signal transduction regulating intimal cell replication in arterial lesion

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1. In order to study the mechanisms of neointimal cell replication, we developed an experimental model of stent implantation to preexisting intimal hyperplasia, which utilized rabbit carotid artery. Briefly, the carotid artery was subjected to ordinary balloon injury with 2F Fogarty catheter, and 28 days later, 3-mm diameter Palmaz stent was implanted in the same carotid artery. Since neointimal hyperplasia had been developed by 28 days after the balloon injury, stent was implanted into the developed intimal lesion, which mimicked clinical setting. The stent implantation promoted intimal cell replication and in-stent lesion formation. Macrophage infiltration around stent strut and leukocyte adhesion to luminal surface were also observed after stent implantation, suggesting that inflammatory reactions played an important role in in-stent lesion formation.2. To investigate how inflammatory reactions in the arterial wall influences intimal lesion formation, we transferred dominant negative (DN) of TRAF-6, potent key component of inflammatory signaling, into the arterial wall by in vivo electroporation method. TRAF-6 DN significantly inhibited medial and intimal cell replication, which was associated with the suppressed activity of ERK1/2 and NF-kB. Further, TRAF-6 DN increased apoptos is in the medial layer, and significantly blocked cell migration from media to intima. These findings indicated that inhibition of inflammatory signaling suppressed intimal lesion formation in the arterial wall.