血管肽抑制球囊剥脱后兔主动脉中的癌基因诱导。

Bauters C, Van Belle E, Wernert N, Delcayre C, Thomas F, Dupuis B, Lablanche J M, Bertrand M E, Swynghedauw B

Department of Cardiology, University of Lille, France.

Circulation. 1994 May;89(5):2327-31. doi: 10.1161/01.cir.89.5.2327.

BACKGROUND

Angiopeptin, a synthetic cyclic octapeptide analogue of somatostatin, reduces neointimal hyperplasia after balloon denudation of rabbit aorta if administered before injury. The aim of this study was to analyze the effect of angiopeptin pretreatment on the level of expression of the c-fos and c-jun protooncogenes, early markers of smooth muscle cell proliferation, after balloon denudation of rabbit aorta.

METHODS AND RESULTS

For histological analysis of the effect of angiopeptin on neointimal thickening after aortic balloon denudation, rabbits were randomized into three groups: group 1 (controls), twice-daily injections of saline begun 24 hours before balloon denudation (n = 9); group 2, twice-daily injections of angiopeptin 10 micrograms/kg begun 24 hours before balloon denudation (n = 9); and group 3, twice-daily injections of angiopeptin 10 micrograms/kg begun 1 hour after balloon denudation (n = 7). The degree of neointimal thickening 28 days after balloon denudation was significantly less in group 2 than in group 1 (neointimal area: group 1, 0.59 +/- 0.11 mm2; group 2, 0.22 +/- 0.05 mm2; P < .05. Neointima/media: group 1, 0.85 +/- 0.17; group 2, 0.23 +/- 0.05; P < .05). When angiopeptin was started 1 hour after denudation (group 3), however, the neointimal area (0.52 +/- 0.09 mm2) and the neointima/media ratio (0.76 +/- 0.10) were not statistically different from the control group. For analysis of protooncogene induction, rabbits received twice-daily subcutaneous injections of saline (n = 7), angiopeptin 10 micrograms/kg (n = 8), or angiopeptin 100 micrograms/kg (n = 4) begun 24 hours before balloon denudation. The animals were killed 30 minutes after balloon denudation, and total aortic RNA was hybridized with fos and jun probes. Expression of c-fos and c-jun was detected 30 minutes after injury; angiopeptin pretreatment at 20 micrograms.kg-1.d-1 induced a 41% reduction in c-fos expression and a 42% reduction in c-jun expression compared with control animals. The inhibitory effect at the higher dose of angiopeptin was similar.

CONCLUSIONS

Our results show that the inhibitory effect of angiopeptin on neointimal thickening is related to events that occur very early after injury and suggest that the inhibition of smooth muscle cell activation may be responsible, at least in part, for this effect.

背景

血管肽素是一种合成的生长抑素环八肽类似物，若在损伤前给药，可减少兔主动脉球囊剥脱术后的内膜增生。本研究旨在分析血管肽素预处理对兔主动脉球囊剥脱术后平滑肌细胞增殖早期标志物c-fos和c-jun原癌基因表达水平的影响。

方法与结果

为了通过组织学分析血管肽素对主动脉球囊剥脱术后内膜增厚的影响，将兔随机分为三组：第1组（对照组），在球囊剥脱前24小时开始每日两次注射生理盐水（n = 9）；第2组，在球囊剥脱前24小时开始每日两次注射10微克/千克血管肽素（n = 9）；第3组，在球囊剥脱后1小时开始每日两次注射10微克/千克血管肽素（n = 7）。球囊剥脱术后28天，第2组内膜增厚程度明显小于第1组（内膜面积：第1组，0.59±0.11平方毫米；第2组，0.22±0.05平方毫米；P <.05。内膜/中膜：第1组，0.85±0.17；第2组，0.23±0.05；P <.05）。然而，当在剥脱后1小时开始注射血管肽素时（第3组），内膜面积（0.52±0.09平方毫米）和内膜/中膜比值（0.76±0.10）与对照组无统计学差异。为了分析原癌基因的诱导情况，在球囊剥脱前24小时开始，兔每日两次皮下注射生理盐水（n = 7）、10微克/千克血管肽素（n = 8）或100微克/千克血管肽素（n = 4）。在球囊剥脱后30分钟处死动物，将主动脉总RNA与fos和jun探针杂交。损伤后30分钟检测到c-fos和c-jun的表达；与对照动物相比，20微克·千克-1·天-1的血管肽素预处理使c-fos表达降低41%，c-jun表达降低42%。更高剂量血管肽素的抑制作用相似。