Department of Cardiology, Royal North Shore Hospital and University of Sydney, St Leonards, NSW 2065, Australia.
Atherosclerosis. 2011 Jan;214(1):65-72. doi: 10.1016/j.atherosclerosis.2010.10.003. Epub 2010 Oct 8.
Restenosis after both angioplasty and stenting is flow dependent. The effects of flow are preventable with the antioxidant pyrrolidine dithiocarbamate (PDTC) after angioplasty but not after stenting. We examined to what extent these observations could be explained by the effect of PDTC on NF-κB and Egr-1, two transcription factors which are both flow- and redox-sensitive.
In a flow-modified rabbit carotid model of angioplasty and stenting, we assessed the effects of altered flow, injury and PDTC on expression of Egr-1 and nuclear binding activity of NF-κB. We also examined the effects of local delivery of decoy oligodeoxynucleotides (ODN) specific for NF-κB and Egr-1 on morphology at 28 days in normal and low flow.
The activity of both transcription factors was enhanced by injury (stent>balloon alone) and was further augmented by low flow. PDTC markedly attenuated the activity of NF-κB but not Egr-1. Specific decoy ODN for Egr-1 attenuated intima formation in both stented and balloon injured vessels in both normal and low flow but had no effect on remodelling. In contrast while NF-κB decoy ODN caused a modest but significant reduction in intima formation, there was a striking effect on remodelling in low flow vessels only.
We conclude that Egr-1 plays a pivotal role in intima formation under all flow conditions and that NF-κB plays a key role in flow-sensitive remodelling after angioplasty and that NF-κB inhibition likely accounts for a significant part of the morphological effects of PDTC after vessel injury.
血管成形术和支架置入术后的再狭窄是依赖血流的。抗氧化剂吡咯烷二硫代氨基甲酸盐（PDTC）可预防血管成形术后的血流作用，但不能预防支架置入术后的血流作用。我们研究了 PDTC 对 NF-κB 和 Egr-1 的作用在多大程度上可以解释这些观察结果，这两种转录因子都对血流和氧化还原敏感。
在改良兔颈动脉球囊血管成形术和支架置入术的血流模型中，我们评估了改变血流、损伤和 PDTC 对 Egr-1 表达和 NF-κB 核结合活性的影响。我们还研究了 NF-κB 和 Egr-1 特异性的诱饵寡脱氧核苷酸（ODN）局部递送至正常和低血流时 28 天的形态学影响。
两种转录因子的活性均因损伤（支架>单纯球囊）而增强，低血流进一步增强。PDTC 明显减弱 NF-κB 的活性，但不减弱 Egr-1 的活性。Egr-1 的特异性诱饵 ODN 可减轻支架置入和球囊损伤血管在正常和低血流中的内膜形成，但对重塑无影响。相反，虽然 NF-κB 诱饵 ODN 导致内膜形成适度但显著减少，但仅在低血流血管中对重塑有显著影响。
我们得出结论，Egr-1 在所有血流条件下的内膜形成中起关键作用，NF-κB 在血管成形术后的血流敏感重塑中起关键作用，NF-κB 抑制可能是血管损伤后 PDTC 形态学作用的重要部分。
