血红素氧合酶-1/一氧化碳与一氧化氮合酶/一氧化氮系统抑制球囊损伤后再狭窄的作用及其相关性研究

Effect and Correlation of Heme Oxygenase-1-Endogenous Carbon Monoxide and Nitrogen Monoxide-Nitricoxide Synthase Systems on Restenosis after Rabbit Carotid Artery Balloon Injury

目的:探讨血红素氧合酶-1(HO-1) /一氧化碳(CO)系统与一氧化氮合酶(NOS) /一氧化氮(NO)系统抑制兔颈动脉球囊损伤后再狭窄的作用和相互关系。方法:家兔随机分为:对照组、胆固醇组、血红素组、卟啉锌组、精氨酸组、亚硝基组和假手术组(每组10只)。对照组予普通饮食,其余6组喂饲含1.5%胆固醇饲料,血红素组和卟啉锌组同时分别给予氯化血红素或锌原卟啉-9腹腔内注射,精氨酸组和亚硝基组同时饮水,给予L-精氨酸或亚硝基-L-精氨酸甲酯,2周后实验组行颈总动脉球囊损伤术,术后继续原方式喂养8周。结果:6组高胆固醇喂养家兔的血脂(TC、TG、LDL、ox-LDL)水平显著升高(P均<0.01)。与对照组比较,胆固醇组颈动脉NO生成量、NOS活性显著降低,而CO生成量、HO-1活性、内膜面积显著增加(P均<0.01)。与胆固醇组比较,血红素组HO-1活性、CO生成量显著增加,内皮素-1(ET-1)水平显著降低,内膜面积和内膜/中膜面积比减小(P均<0.01);卟啉锌组HO-1活性、CO生成量明显降低,ET-1水平、内膜面积和内膜/中膜面积比显著增加(P均<0.01);精氨酸组cNOS活性、NO生成量显著增加,ET-1水平,内膜面积和内膜/中膜面积比明显降低(P均<0.01);亚硝基组cNOS活性、NO生成量明显降低,ET-1水平、内膜面积和内膜/中膜面积比显著增加(P均<0.01)。结论:HO-1 / CO与NOS/NO系统均有抑制再狭窄的作用,两系统作用互补且相互代偿,HO-1 /CO系统通过调节和代偿NOS、NO以及下调ET-1而抑制血管损伤后再狭窄。

Objective:To investigate the effect and correlation of heme oxygenase-1(HO-1)/carbon monoxide(CO) and nitricoxide synthase(NOS)/nitrogen monoxide(NO) systems on the restenosis after balloon angioplasty.Method:Seventy rabbits were randomly divided into 7 groups of 10 rabbits:control group received normal chow(C group),the other rabbits received 1.5% cholesterol diet (Ch group and SH group) or 1.5% cholesterol diet plus hemin(Hm group) or zincprotoporphyrin IX(Zn group) or L-arginine(Arg group) or L-nitro-arginine methylester (L-NAME group) for 10 weeks.At the beginning of 3 rd week,Ch,Hm,Zn,Arg and L-NAME groups underwent balloon injury at one side carotid artery.Results:High cholesterol diet markedly enhanced the levels of serum TC,TG,LDL-C and ox-LDL (all P<0.01).However,there were not much different among these six experimental groups.Compared with control group,arterial NO production and cNOS activity decreased markedly,while CO production and HO activity increased markedly(all P<0.01) in Ch group.Compared with Ch group,CO production and HO-1 activity increased markedly in Hm group,while in Zn group they decreased markedly.Exdogenous L-arginine eleveated markedly cNOS activity and NO production,exdogenous L-NAME made the opposite results.Compared with Ch group,ET-1 leves of Hm group and Arg group reduced markedly while in Zn group and L-NAME group they were higher significantly than Ch group.The intima area and ratio of intima/media(I/M) were reduced distinctly in Hm group( 0.386±0.076,0.862±0.164 respectively) and Arg group(0.425±0.082,0.915±0.183 respectively),while in Zn group and L-NAME group they were distinctly increased\[(0.734±0.096,1.843±0.212);(0.630±0.098,1.435±0.192)respectively\].Conclusion:HO-1/CO and NOS/NO systems play an inhibitory role against vascular wall remodeling.This role is related to the reciprocal relationship between HO-1/CO and NOS/NO system in restenosis and the down-regulated expression of ET-1.