MITHRAMYCIN INHIBITS MYOINTIMAL PROLIFERATION AFTER BALLOON INJURY OF THE RAT CAROTID-ARTERY IN-VIVO
MITHRAMYCIN INHIBITS MYOINTIMAL PROLIFERATION AFTER BALLOON INJURY OF THE RAT CAROTID-ARTERY IN-VIVO
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DOI：
10.1161/01.cir.90.5.2468
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发表时间：
1994-11-01
期刊：
影响因子：
37.8
通讯作者：
OPARIL, S
中科院分区：
文献类型：
--
作者：
CHEN, SJ;CHEN, YF;OPARIL, S
背景：血管内膜损伤后内膜下平滑肌增生和细胞外基质形成是导致冠状动脉球囊成形术后再狭窄和加速其他病理生理状态下动脉粥样硬化的原因。立即早期反应基因c-myc在体外增殖的血管平滑肌细胞中过表达，并且c-myc反义寡聚体已显示出降低c-myc表达并抑制培养的血管平滑肌细胞的增殖。光神霉素是一种市售的G-C特异性DNA结合药物，可选择性抑制具有富含G-C启动子序列的基因（如c-myc）的转录。本研究测试的假设，即光辉霉素抑制c-myc原癌基因的转录，并防止肌内膜增殖后，大鼠颈动脉invivo.Methods和结果的球囊损伤的大鼠颈动脉10周龄的雄性Sprague-Dawley大鼠接受光辉霉素（150 μ g/kg IF）或蒸馏水1小时前和1小时后球囊损伤的右颈总动脉。2周后，通过过量的戊巴比妥处死大鼠，将损伤的右动脉和未损伤的对照左动脉压力固定，并进行形态学分析以评价肌内膜增厚的程度。在血管损伤后2和6小时处死各组大鼠，对来自光神霉素和溶剂处理大鼠的损伤和对照血管的总RNA进行北方分析，以评估稳态c-myc mRNA水平。与对照组大鼠相比，经mithramycin治疗的大鼠的新生内膜面积和新生内膜与中膜面积的比值明显更小（0.6+/-0.1mm2 vs 1.2+/-0.1mm2，P
Background Smooth muscle proliferation and extracellular matrix formation in the subintimal region of blood vessels that have been subjected to intimal injury are responsible for restenosis following balloon angioplasty of the coronary arteries and for accelerated atherosclerosis in a variety of other pathophysiological states. The immediate early-response gene c-myc is overexpressed in proliferating vascular smooth muscle cells in vitro, and c-myc antisense oligomers have been shown to reduce c-myc expression and to inhibit proliferation of vascular smooth muscle cells in culture. Mithramycin is a commercially available G-C-specific DNA binding drug that selectively inhibits transcription of genes, such as c-myc, that have G-C-rich promoter sequences. This study tested the hypothesis that mithramycin inhibits transcription of the c-myc proto-oncogene and prevents myointimal proliferation after balloon injury of the rat carotid artery in vivo.Methods and Results Ten-week-old male Sprague-Dawley rats received mithramycin (150 mu g/kg IF) or distilled H2O 1 hour before and 1 hour after balloon injury of the right common carotid artery. After 2 weeks, the rats were killed by overdose of pentobarbital, and the injured right and uninjured control left arteries were pressure-fixed and subjected to morphological analysis for evaluation of the degree of myointimal thickening. Separate groups of rats were killed at 2 and 6 hours after vascular injury, and total RNA from injured and control vessels of mithramycin- and vehicle-treated rats was subjected to Northern analysis for assessment of steady-state c-myc mRNA levels. The areas of neointima and the ratios of neointimal to medial area were significantly less in mithramycin-treated than in control rats (0.6+/-0.1 versus 1.2+/-0.1 mm(2), P