洛伐他汀对同型半胱氨酸硫内酯所致大鼠离体胸主动脉内皮损伤的保护作用

Protective Effects of Lovastatin on Endothelial Impairment Induced by Homocyteine Thiolactone in Rat Isolated Aorta

目的观察洛伐他汀对同型半胱氨酸硫内酯所致大鼠离体胸主动脉内皮损伤的保护作用并探讨其相关机制。方法用同型半胱氨酸硫内酯与大鼠离体胸主动脉血管环共孵育90min诱导血管内皮损伤,检测血管内皮依赖性、非内皮依赖性舒张反应以及血管组织生物化学指标,观察洛伐他汀对同型半胱氨酸硫内酯诱导的血管内皮功能损伤的影响。结果血管环与同型半胱氨酸硫内酯孵育90min后,乙酰胆碱诱导的内皮依赖性舒张反应明显降低,而硝普钠引起的非内皮依赖性舒张反应无明显改变;血管组织中丙二醛浓度显著增加,超氧化物歧化酶活性下降,一氧化氮含量减少,与正常对照组相比差异有显著性(P<0.05);给予洛伐他汀10、20和40μmol/L可明显减轻同型半胱氨酸硫内酯对离体胸主动脉血管环内皮依赖性舒张反应的损伤,使Emax从39.72%±1.91%分别升至54.84%±1.89%、66.25%±1.93%和80.12%±1.32%,半数有效浓度从230.45±13.42nmol/L分别降至145.34±13.19nmol/L、126.93±12.91nmol/L和109.16±14.20nmol/L,一氧化氮水平从0.26±0.04mmol/g分别升至0.51±0.05、0.67±0.03和0.88±0.04mmol/g,同时血管组织中丙二醛含量明显降低,超氧化物歧化酶活性升高,与同型半胱氨酸硫内酯损伤组相比差异均有显著性(P<0.05或P<0.01)。超氧化物歧化酶、N-乙酰半胱氨酸、左旋精氨酸也有和洛伐他汀相类似的抗同型半胱氨酸硫内酯损伤作用,而L-N-硝基精氨酸甲酯可拮抗洛伐他汀的抗同型半胱氨酸硫内酯的损伤作用。结论洛伐他汀能拮抗同型半胱氨酸硫内酯对血管内皮功能的损伤作用,其机制可能与抑制氧化应激、保护血管内皮的一氧化氮合成与释放有关。

Aim To explore the protective effect of lovastatin on endothelial dysfunction induced by homocysteine thio-lactone （HTL） and potential mechanism. Methods 90 min after the co-incubation of aorta rings with various agents, both the acetylcholine （Ach）-induced endothelium-dependent relaxation （EDR） and sodium nitroprusside （SNP）-induced endothelium-independent relaxation of aortic rings were examined, and the biochemical parameters including content of malondialdehyde （MDA）, level of nitric oxide （NO） and activity of superoxide dismutase （SOD） in vascular tissue were also measured. Results After incubation with HTL for 90 minutes, Ach-induced EDR was significantly decreased, while SNP-induced endothelium- independent relaxation was not affected. HTL also markedly reduced the levels of NO and SOD activity, and increased the content of MDA in rat aorta tissue, compared with normal control group （P〈0.05）. The lovastatin 10, 20 and 40 μmol/L improved the EDR, the Emax was increased from 39.72%±1.91% to 54.84%±1.89%, 66.25%±1.93%, 80.12%±1.32% respectively; half effective concentration （EC50 ） was decreased from 230.45±13.42 nmol/L to 145.34±13.19 nmol/L, 126.93± 12.91 nmol/L, 109.16±14.20 nmol/L respectively; while the NO level was increased from 0.26±0.04 mmol/g to 0.51±0.05 mmol/g, 0.67 ±0.03 mmol/g, 0.88±0.04 mmol/g; The lovastatin also decreased the MDA level and maintained SOD activity induced by HTL in rat aorta compared with alone HTL group （P〈0.05 or 0.01）. However, the incorporating of lovastatin with L-NAME abolished the protective effect of lovastatin on endothelial function damaged by HTL. SOD, the antioxidant NAC and the nitric oxide precursor L-arginine also ameliorated the impaired EDR induced by HTL. Conclusion Lovastatin can protect from endothelial function injury by HTL.The mechanism may be related to protecting release of NO and suppressing the generation of oxygen-free radicals.