1型多聚ADP核糖聚合酶抑制剂对高同型半胱氨酸血症大鼠内皮功能的保护作用

Prevention of hyperhomocysteinemia-induced endothelial dysfunction by poly ADP-ribose polymerase 1 inhibition in the rat

目的:探讨1型多聚ADP核糖聚合酶(PARP1)抑制剂3-氨基苯甲酰胺(3-AB)对高同型半胱氨酸血症(Hhcy)大鼠内皮功能的保护作用。方法:SD大鼠30只随机分为3组:模型组、3-AB组和正常对照组,每组10只,分别给予普通饲料加1.7%蛋氨酸、普通饲料加1.7%蛋氨酸同时每天腹腔注射3-AB20mg·kg-1和普通饲料,饲养45d。观察主动脉组织形态结构的改变;测定血浆同型半胱氨酸(Hcy)、内皮素-1(ET-1)和一氧化氮(NO)的水平;检测大鼠胸主动脉环对乙酰胆碱(Ach)与硝普钠(SNP)的反应;检测大鼠胸主动脉PARP1蛋白的表达。结果:大鼠喂以高蛋氨酸饲料45d可诱导Hhcy。与模型组相比3-AB组大鼠NO水平明显升高而ET-1水平明显降低(P<0.01)。病理形态学观察模型组主动脉内膜病变明显,3-AB组病变程度减轻。与正常对照组比较,模型组胸主动脉对Ach引起的最大的内皮依赖性舒张反应(EDR)明显减弱(0.26±0.03vs0.89±0.11,P<0.01);而3-AB组EDR反应较模型组显著改善(0.57±0.12vs0.26±0.03,P<0.01)。模型组较正常对照组大鼠主动脉PARP表达明显升高(P<0.05),3-AB组PARP表达较模型组明显降低(P<0.05)。结论:PARP抑制剂3-AB有效地改善高同型半胱氨酸血症大鼠血管内皮功能,并在一定程度上改善血管早期病理形态学的改变。

AIM： To investigate the possible protective effect of pharmacological inhibition of poly ADP - ribose polymerase 1 （ PARPl ） in preventing endothelial dysfunction of rats with hyperbomocysteinemia. METHODS ： Male Sprague - Dawley rats （ n = 30） were randomly divided into 3 groups ： Hhcy group, 3 - aminobenzamide （ 3 - AB） treated group and control group. A high - methionine diet was used in both Hhcy group and 3 - AB group to induce hyperhomocys- teinemia. In 3 - AB group, the rats were injected intraperitoneally with 3 - AB （ a prototypical pharmacological inhibitor of PARP1 ） for 45 d. Morphological changes of aortas were observed by light microscopy and transmission electron microscope. The levels of plasma total bomocysteine, NO and ET - 1 were measured. Vascular reactivity of thoracic aortic rings was measured in organ chambers. The level of PARP 1 expression was detected by Western blotting. RESULTS： Rats in Hhcy group developed severe hyperhomocysteinemia. The significant endothelial dysfunction as measured by both the relaxant responsiveness of vascular rings to Ach and the levels of NO and ET - 1 was observed. Treatment with 3 - AB did not influence hyperhomocysteinemia, but improved Ach - induced, NO - mediated vascular relaxation and stabilized the level of NO and ET - 1. Obvious improvement of morphology and ultrastructure were also observed in 3 - AB group compared with that in Hhcy group. Western blotting analysis showed 3 - AB significantly decreased the expression of PARP1. CONCLUSION ： These results suggest that pharmacological inhibition of PARP prevents the development of the endothelial dysfunction in rats with hyperhomocysteinemia, which may represent a novel approach to improve vascular dysfunction associated with hyperhomocysteinemia.