瑞舒伐他汀在高同型半胱氨酸血症诱导大鼠动脉粥样硬化中对基因组甲基化影响

Effect of rosuvastatin on global DNA methylation in ratsatherosclerosis induced by hyperhomocysteinemia

目的:探讨瑞舒伐他汀在高同型半胱氨酸血症(HHcy)诱导大鼠主动脉粥样硬化(AS)中对基因组总甲基化的影响。方法:健康6周龄雄性Wistar大鼠48只,随机分为对照组、HHcy组、瑞舒伐他汀低剂量干预组(RL组)和瑞舒伐他汀高剂量干预组(RH组),每组12只。喂养24周后,通过全自动生化分析仪测定血浆Hcy浓度及血脂浓度;观察主动脉形态学变化;检测基因组DNA总甲基转移酶(DNMTs)活性和基因组DNA总甲基化水平。结果:RL组和RH组血浆Hcy浓度均降低(P<0.01),同时可以逆转HHcy诱导的主动脉组织形成的纤维斑块,但RL组和RH组比较,主动脉病理学改变不明显;HHcy组主动脉DNMTs活性和基因组总甲基化水平明显低于对照组(P<0.01);RL组和RH组主动脉DNA总甲基化水平和DNMTs活性较HHcy组明显升高(P<0.01),而且,RH组较RL组更明显(P<0.05)。结论:瑞舒伐他汀可能通过降低血浆Hcy水平,诱导基因组DNMTs活性升高,致使基因组DNA总甲基化水平升高,进而发挥抗AS的作用。

Objective：To investigate the effects of rosuvastatin on global DNA methylation in rats atherosclerosis induced by hyperhomocysteinemia（HHcy）. Method：The 48 healthy 6-week-old Wistar male rats were randomly divided into control group（n=12）,HHcy group（n=12）,rosuvastatin low dose treatment group（RL;n=12） and rosuvastatin high dose treatment group（RH;n=12）.After be maintained for 24 weeks,the homocysteine（Hcy） and lipid concentrations in the plasma were measured with the IMX assays.The thoracic aorta was harvested for morphology（HE staining）.Extraction aorta tissue global DNA and nuclear extracts,then we measured the DNA methyltransferase activity and global DNA methylation levels. Result：A high methionine intragastric administration for 24 weeks was sufficient to induce HHcy and atherosclerosis.Posuvastatin could prevent an ele-vation Hcy levels in the plasma（P0.01） and be reversed HHcy induction of aortic organization fiber patch formation.But compared with the RH group,pathology change was not obvious in RL group.Compared with control group,the HHcy group had decreased DNA methyltransferase activity and global DNA methylation levels（P0.01）.Most important,after rosuvastatin supplementation,the DNA methyltransferase activity and the global DNA methylation levels rised obviously（P0.01）,and the RH group more obviously than RL group（P0.05）. Conclusion：Rosuvastatin can decrease Hcy levels in the plasma and then increase DNA methyltransferase activity and global DNA methylation for AS.