Signal transduction regulating intimal cell replication in arterial lesion

1. 为了研究新生内膜细胞复制的机制，我们建立了兔颈动脉内膜增生支架植入术的实验模型。简单地说，用2F Fogarty导管对颈动脉进行普通球囊损伤，28天后在同一颈动脉内植入3mm直径的Palmaz支架。由于球囊损伤后28天出现内膜增生，因此将支架植入已形成的内膜病变处，模拟临床情况。支架植入促进内膜细胞复制和支架内病变形成。支架植入术后，支架支架周围可见巨噬细胞浸润，白细胞粘附于管腔表面，提示炎症反应在支架内病变形成中起重要作用。为了研究动脉壁的炎症反应如何影响内膜病变的形成，我们通过体内电穿孔法将炎症信号的关键成分TRAF-6的显性阴性（DN）转移到动脉壁。TRAF-6 DN显著抑制内侧和内膜细胞复制，这与抑制ERK1/2和NF-kB活性有关。此外，TRAF-6 DN增加了内层的凋亡，并显著阻断了细胞从中膜向内膜的迁移。这些结果表明，炎症信号的抑制抑制了动脉壁内膜病变的形成。

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.