洛伐他汀对HTL所致血管内皮功能损伤的保护作用及机制探讨
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摘要
目的探讨洛伐他汀对同型半胱氨酸硫内酯(HomocysteineThiolactone,HTL)所致大鼠血管内皮功能损伤的保护作用及机制。
方法实验分为离体实验和在体实验(1)离体实验部分:按文献方法制备大鼠离体胸主动脉环,实验分10组①正常对照组;②洛伐他汀(40μmol/L)对照组;③HTL(30mmol/L)损伤组;④～⑥HTL(30mmol/L)+洛伐他汀(10,20,40μmol/L)保护组;⑦HTL(30mmol/L)+洛伐他汀(40μmol/L)+L-N-硝基精氨酸甲酯(L-N-nitro-arginine methylester,L-NAME0.01mmol/L)组;⑧HTL(30mmol/L)+N-乙酰半胱氨酸(N-acetylcysteine,NAC 0.05 mmol/L)组;⑨HTL(30mmol/L)+左旋精氨酸(L-arginine,L-Arg 3 mmol/L)组;⑩HTL(30mmol/L)+超氧化物歧化酶(superoxide dismutase,SOD 200U/ml)组。血管环与各处理因素共同孵育90 min,检测乙酰胆碱(acetylcholine,ACh)诱导的内皮依赖性舒张反应(endothelium-dependent relaxation,EDR)和硝普钠(sodiumnitroprusside,SNP)诱导的非内皮依赖性舒张反应。同时检测血管组织中的各项生化指标。(2)在体实验部分:将42只雄性SD大鼠随机分为7组(n=6),分别接受不同药物灌胃8周。8周后放血处死动物取胸主动脉和血清标本,检测EDR及非内皮依赖性舒张反应,同时检定血清中的各项生化指标。
结果(1)离体实验:HTL(30mmol/L)与血管环共孵90min,明显抑制了ACh诱导的EDR,而对SNP诱导的非内皮依赖性舒张反应无明显影响;HTL在抑制大鼠胸主动脉EDR的同时,增加了血管组织中MDA的含量、降低了NO水平及SOD的活性;洛伐他汀(10,20,40μmol/L、)呈浓度依赖性地减轻了HTL对大鼠胸主动脉EDR的抑制作用,洛伐他汀(40μmol/L)明显抑制了HTL所致的血管组织中MDA含量的升高,减轻了HTL所致的NO水平、SOD活性的降低;NO合酶抑制剂L-NAME可部分取消洛伐他汀对血管EDR的保护作用;而L-Arg、NAC、SOD则能显著减轻HTL对血管EDR的损伤作用、增加NO的水平及SOD的活性,减少血管组织中MDA含量。(2)在体实验:实验表明HTL灌胃8周后导致大鼠胸主动脉的EDR降低,而对SNP诱导的非内皮依赖性舒张反应无明显影响,血清中NO水平、谷胱甘肽过氧化物酶(GSH-Px)与SOD活性显著降低、MDA含量及血管内皮中NF-κBP65的表达增加;洛伐他汀呈剂量依赖性保护了HTL损伤的大鼠胸主动脉EDR,显著抑制了血管内皮中NF-κBP65的表达;减轻了HTL对血清NO水平、GSH-Px与SOD活性的抑制,减少了血清MDA浓度的升高;各组大鼠血清脂蛋白水平无明显变化。
结论洛伐他汀对外源性HTL所致的离体、在体大鼠血管内皮舒张功能的损伤均有显著性保护作用,其作用机制不依赖其降胆固醇作用,可能与洛伐他汀的抗氧化作用有关。
AIM To explore the protective effects and mechanisms of lovastatin on impairment of vascular endothelium function in rats induced by homocysteine thiolactone(HTL).
METHODS(1)In vitro experiment:The isolated thoracic aorta rings of rat were prepared according to previous methods.The rings were respectively incubated for 90 min with Krebs-Henseleit solusion(K-H) which contained-different agents including HTL(30mmol/L)alone, lovastatin(40μmol/L)alone,HTL plus lovastatin(10,20 or 40μmol/L), HTI,plus L-NAME(0.01 mmol/L)and l ovastatin(40gmol/L),HTL plus NAC(0.05 mmol/L),HTL plus L-arginine(3 mmol/L),HTL plus SOD (200 U/ml).After 90min,the EDR and non-dependent relaxation of thoracic arteries and biochemical index in tissue of vessels were measured.(2)In vivo experiment,the 42 SD rats were randomly divided into seven groups(n=6),and respectively received a gavage of normal salin contained-different drugs for 8 weeks.After 8 weeks,the rats were sacrificed by exanguinate,thoracic arteries and blood sample were got. EDR and non-dependent relaxation of thoracic arteries and biochemical index in sera were measured.
RESULTS(1)Results of the experiments in vitro:An incubation of aortic rings for 90 min with HTL(30 mmol/L)resulted in a significant inhibition of EDR,Simultaneously resulted in increase of MDA concentration,decrease of NO contents and the activity of SOD in aortic tissue,but endothelium-independent relaxation was not affected. Lovastatin(10,20 or 40μmol/L)signifecantly protected EDR,and Lovastatin(40μmol/L)attenuated the decrease of NO content and the activity of SOD as well as elevation of MDA concentration in aortic tissue caused by HTL.L-NAME,a nitric oxide synthase inhibitor,partly blocked the protective effects of lovastatin.The NAC and SOD and L-arginine significantly improved endothelial function and biochemical reference injured by HTL.(2)the experiment in vivo,HTL significantly inhibited EDR and simultaneously combined with decrease of NO level,activity of glutathioneperoxidase and SOD as well as increased the content of MDA in sera,stimulated the activation of NF-κBP65 of vascular endothelium in rats.Lovastatin markedly improved the EDR response,simultaneously inhibited the activation of NF-κBP65 of vascular endothelium,maintained the content of NO,glutathione peroxidase and SOD and decrease of MDA content in sera.HTL and Lovastatin had no effect on endothelium-independent relaxation in rat arteries.There are no significant difference in the lipoprotein serum level among all the groups.
CONCLUSION The results in vitro and in vivo demonstrated that Lovastatin could significantly protect from impairment of vascular endothelium function in rats induced by HTL.The mechanism may relate to anti-oxidation effects of lovastatin,not depend on its cholesterollowing manner.
方法实验分为离体实验和在体实验(1)离体实验部分:按文献方法制备大鼠离体胸主动脉环,实验分10组①正常对照组;②洛伐他汀(40μmol/L)对照组;③HTL(30mmol/L)损伤组;④～⑥HTL(30mmol/L)+洛伐他汀(10,20,40μmol/L)保护组;⑦HTL(30mmol/L)+洛伐他汀(40μmol/L)+L-N-硝基精氨酸甲酯(L-N-nitro-arginine methylester,L-NAME0.01mmol/L)组;⑧HTL(30mmol/L)+N-乙酰半胱氨酸(N-acetylcysteine,NAC 0.05 mmol/L)组;⑨HTL(30mmol/L)+左旋精氨酸(L-arginine,L-Arg 3 mmol/L)组;⑩HTL(30mmol/L)+超氧化物歧化酶(superoxide dismutase,SOD 200U/ml)组。血管环与各处理因素共同孵育90 min,检测乙酰胆碱(acetylcholine,ACh)诱导的内皮依赖性舒张反应(endothelium-dependent relaxation,EDR)和硝普钠(sodiumnitroprusside,SNP)诱导的非内皮依赖性舒张反应。同时检测血管组织中的各项生化指标。(2)在体实验部分:将42只雄性SD大鼠随机分为7组(n=6),分别接受不同药物灌胃8周。8周后放血处死动物取胸主动脉和血清标本,检测EDR及非内皮依赖性舒张反应,同时检定血清中的各项生化指标。
结果(1)离体实验:HTL(30mmol/L)与血管环共孵90min,明显抑制了ACh诱导的EDR,而对SNP诱导的非内皮依赖性舒张反应无明显影响;HTL在抑制大鼠胸主动脉EDR的同时,增加了血管组织中MDA的含量、降低了NO水平及SOD的活性;洛伐他汀(10,20,40μmol/L、)呈浓度依赖性地减轻了HTL对大鼠胸主动脉EDR的抑制作用,洛伐他汀(40μmol/L)明显抑制了HTL所致的血管组织中MDA含量的升高,减轻了HTL所致的NO水平、SOD活性的降低;NO合酶抑制剂L-NAME可部分取消洛伐他汀对血管EDR的保护作用;而L-Arg、NAC、SOD则能显著减轻HTL对血管EDR的损伤作用、增加NO的水平及SOD的活性,减少血管组织中MDA含量。(2)在体实验:实验表明HTL灌胃8周后导致大鼠胸主动脉的EDR降低,而对SNP诱导的非内皮依赖性舒张反应无明显影响,血清中NO水平、谷胱甘肽过氧化物酶(GSH-Px)与SOD活性显著降低、MDA含量及血管内皮中NF-κBP65的表达增加;洛伐他汀呈剂量依赖性保护了HTL损伤的大鼠胸主动脉EDR,显著抑制了血管内皮中NF-κBP65的表达;减轻了HTL对血清NO水平、GSH-Px与SOD活性的抑制,减少了血清MDA浓度的升高;各组大鼠血清脂蛋白水平无明显变化。
结论洛伐他汀对外源性HTL所致的离体、在体大鼠血管内皮舒张功能的损伤均有显著性保护作用,其作用机制不依赖其降胆固醇作用,可能与洛伐他汀的抗氧化作用有关。
AIM To explore the protective effects and mechanisms of lovastatin on impairment of vascular endothelium function in rats induced by homocysteine thiolactone(HTL).
METHODS(1)In vitro experiment:The isolated thoracic aorta rings of rat were prepared according to previous methods.The rings were respectively incubated for 90 min with Krebs-Henseleit solusion(K-H) which contained-different agents including HTL(30mmol/L)alone, lovastatin(40μmol/L)alone,HTL plus lovastatin(10,20 or 40μmol/L), HTI,plus L-NAME(0.01 mmol/L)and l ovastatin(40gmol/L),HTL plus NAC(0.05 mmol/L),HTL plus L-arginine(3 mmol/L),HTL plus SOD (200 U/ml).After 90min,the EDR and non-dependent relaxation of thoracic arteries and biochemical index in tissue of vessels were measured.(2)In vivo experiment,the 42 SD rats were randomly divided into seven groups(n=6),and respectively received a gavage of normal salin contained-different drugs for 8 weeks.After 8 weeks,the rats were sacrificed by exanguinate,thoracic arteries and blood sample were got. EDR and non-dependent relaxation of thoracic arteries and biochemical index in sera were measured.
RESULTS(1)Results of the experiments in vitro:An incubation of aortic rings for 90 min with HTL(30 mmol/L)resulted in a significant inhibition of EDR,Simultaneously resulted in increase of MDA concentration,decrease of NO contents and the activity of SOD in aortic tissue,but endothelium-independent relaxation was not affected. Lovastatin(10,20 or 40μmol/L)signifecantly protected EDR,and Lovastatin(40μmol/L)attenuated the decrease of NO content and the activity of SOD as well as elevation of MDA concentration in aortic tissue caused by HTL.L-NAME,a nitric oxide synthase inhibitor,partly blocked the protective effects of lovastatin.The NAC and SOD and L-arginine significantly improved endothelial function and biochemical reference injured by HTL.(2)the experiment in vivo,HTL significantly inhibited EDR and simultaneously combined with decrease of NO level,activity of glutathioneperoxidase and SOD as well as increased the content of MDA in sera,stimulated the activation of NF-κBP65 of vascular endothelium in rats.Lovastatin markedly improved the EDR response,simultaneously inhibited the activation of NF-κBP65 of vascular endothelium,maintained the content of NO,glutathione peroxidase and SOD and decrease of MDA content in sera.HTL and Lovastatin had no effect on endothelium-independent relaxation in rat arteries.There are no significant difference in the lipoprotein serum level among all the groups.
CONCLUSION The results in vitro and in vivo demonstrated that Lovastatin could significantly protect from impairment of vascular endothelium function in rats induced by HTL.The mechanism may relate to anti-oxidation effects of lovastatin,not depend on its cholesterollowing manner.
引文
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