摘要
目的探讨同型半胱氨酸硫内酯所致血管内皮功能损伤机制与过氧化体增殖物激活型受体γ活化的关系。方法以血管内皮依赖性和非内皮依赖性及血管组织和血清的生化参数为观察指标,采用与血管环直接孵育法和在体动物灌胃给药法,观察硫内酯对大鼠血管内皮功能的损伤作用,并探讨其机制。结果硫内酯(10mmol/L)与离体大鼠胸主动脉共孵60 min能显著降低乙酰胆碱引起的内皮依赖性舒张反应,降低血管组织中一氧化氮含量,升高超氧化物歧化酶活性和丙二醛含量(P<0.01)。血管环与硫内酯共孵之前先与罗格列酮(1mmol/L)预孵30 m in,能显著改善被硫内酯降低的血管环内皮依赖性舒张反应,恢复血管环组织中一氧化氮含量,抵抗硫内酯诱导的超氧化物岐化酶活性和丙二醛含量的升高(P<0.05或P<0.01)。卡托普利(0.03 mmol/L)和夹竹桃麻素(0.03 mmol/L)有与罗格列酮相似的作用。在体实验表明,大鼠接受硫内酯[50 mg/(kg.d)]灌胃8周,导致血管内皮依赖性舒张反应明显降低,血清丙二醛含量显著升高,对氧磷酶1活性和一氧化氮含量显著降低(P<0.01),但血清中总一氧化氮合酶活性、内皮型一氧化氮合酶活性、诱导型一氧化氮合酶活性、红细胞超氧化物岐化酶活性与正常对照组比无明显改变(P>0.05)。同时给予罗格列酮[10、20和40 mg/(kg.d)]灌胃8周,可剂量依赖性地保护硫内酯损伤的内皮依赖性舒张反应,降低血清丙二醛含量,升高血清一氧化氮含量和对氧磷酶1活性(P<0.05或P<0.01)。卡托普利[20 mg/(kg.d)]和夹竹桃麻素[200 mg/(kg.d)]灌胃8周,也能保护硫内酯所损伤的血管内皮依赖性舒张反应和恢复硫内酯所改变的生化指标(P<0.05或P<0.01)。在离体和在体实验中,各处理因素对硝普钠引起的非内皮依赖性舒张反应无明显影响(P>0.05)。结论同型半胱氨酸硫内酯在体内和体外均可引起血管内皮功能损伤,其机制可能与抑制过氧化体增殖物激活型受体γ的活性或下调其表达,继而诱发体内氧化应激反应有关。
Aim To explore whether homocysteine thiolactone（HTL）-induced vascular endothelial dysfunctions relate to activation of peroxisome proliferator activated receptor-γ（PPARγ）.Methods The endothelium-dependent relaxation（EDR） and non-endothelium-dependent relaxation（n-EDR） of aortic rings in rats induced by acetylcholine and sodium nitroprusside（SNP） were examined respectively.The various biochemical parameters in vascular tissues or blood sera were also analyzed.Results Incubating HTL（10 mmol/L） with aortic rings for 30 min significantly inhibited EDR of isolated aortic rings,reduced nitro oxide（NO） content,increased activity of superoxide dismutase（SOD） and content of malondialdehyd（MDA） in vitro（P0.01）.The incubation of rosiglitazone（1 mmol/L） with aortic rings for 30 minutes prior to adding HTL significantly lessened HTL induced-injuries of EDR,preserved NO content,inhibited elevation of SOD activity and MDA content in aortic tissues（P0.05 or P0.01）.Incubation of Captopril（0.03 mmol/L） and Apocynin（0.03 mmol/L） with aortic rings for 30 minutes prior to adding HTL respectively also protected the vascular endothelium from injury and the change of biochemistry parameters in aortic tissues（P0.05 or P0.01） in vitro.Rats were administered HTL（50 mg/（kg·d）） by gavage for 8 weeks that resulted in an inhibition of EDR of aortic rings,increases of MDA content,reduction of both paraoxonase-1（PON1） activity and NO content（P0.01）,but had no effect on activity of total nitric oxide synthase（TNOS）,activity of endothelial nitric oxide synthase（eNOS）,activity of induced nitric oxide synthase（iNOS） in sera and activity of erythrocytic SOD（P0.05）.The treatment of rosiglitazone（10,20 or 40 mg/（kg·d）） by gavage prior to gavage of HTL dose-dependently improved EDR of aortic rings injured by HTL in vivo,inhibited elevation of MDA content,recovered PON1 activity and NO content in sera induced by HTL（P0.05 or P0.01）.The treatment of capropril（20 mg/（kg·d）） and apocynin（200 mg/（kg·d）） also significantly reduced injury of EDR and the changes of biochemistry parameters in sera（P0.05 or P0.01）.The treatment of HTL in both vivo and vitro had no effect on the non-endothelium-dependent relaxation by SNP（P0.05）.Conclusion HTL-induced vascular endothelial dysfunction may relate to oxidative stress and involve in inhibiting the activation of PPARγ or down-regulating the expression of PPARγ.
出处
《中国动脉硬化杂志》
CAS
CSCD
北大核心
2009年第12期975-979,共5页
Chinese Journal of Arteriosclerosis
基金
湖南省卫生厅课题(B2008-023)
长沙市科技局课题(K0802085-31)
