阿托伐他汀对自发性高血压大鼠血压和细胞色素P450表氧化酶2C11基因表达的影响

目的研究阿托伐他汀降低自发性高血压大鼠(SHR)血压的作用是否与其调节细胞色素P450表氧化酶2C11(CYP2C11)基因表达的作用有关。方法18只SHR随机分为SHR模型组、阿托伐他汀50和10 mg.kg-1组;6只W istar-Kyoto大鼠(WKY)作为正常对照组。阿托伐他汀ig给药,每日1次,共10周。分别于给药前和给药后每2周测量大鼠尾动脉收缩压(SBP);RT-PCR和W estern印迹法分别检测心、肝、肾及主动脉组织中CYP2C11mRNA和蛋白质表达;ELISA方法检测尿液中14,15二-氢二十碳三烯酸(DHET)含量;并测定血脂含量。结果阿托伐他汀50 mg.kg-1组在给药后第6~10周和10 mg.kg-1组在给药后第10周SBP明显低于SHR模型组。在CYP2C11 mRNA和蛋白质表达中,SHR模型组心、肾和主动脉均明显高于WKY组;给药10周后,阿托伐他汀50 m.gkg-1组的4种组织和10 m.gkg-1组的心、肾和主动脉的表达明显高于SHR模型组。治疗前SHR各组尿液中DHET的含量均显著高于WKY组,给药后阿托伐他汀50 m.gkg-1组的含量明显高于SHR模型组;同时,阿托伐他汀50 mg.kg-1组血脂水平明显低于SHR模型组。结论阿托伐他汀可上调CYP2C11基因的表达,并增加其代谢产物表氧化二十碳三烯酸,这可能是其降低血压的作用机制之一。

Effects of atorvastatin on expression of cytochrome P450 epoxygenase 2C11 in spontaneously hypertensive rats

AIM To investigate if the effect of atorvastatin on blood pressure is related to the expression of cytochrome P450 epoxygenase 2C11 (CYP2C11) in spontaneously hypertensive rats (SHR). METHODS SHR (n=18) were randomly divided into SHR model group, atorvastatin (10 and 50 mg·kg^-1, ig, once daily for 10 weeks) treated groups. Six male Wistar-Kyoto (WKY) rats were selected as normal control group. Systolic blood pressure (SBP) was measured before and every 2 weeks after treatment. The expression of CYP2C11 mRNA and protein in heart, liver, kidney, and aorta were detected by RT-PCR and Western blot analysis, respectively. Urinary 14,15-dihydroxyeicosatrienoic acid (DHET) excretion was quantified by ELISA method. Plasma lipids were also measured. RESULTS SBP in all SHR groups was much higher than that in WKY group before experiment. Compared with SHR model group, SBP significantly decreased after treatment with 50 mg·kg^-1 atorvastatin for 6, 8 and 10 weeks and after treatment with 10 mg·kg^-1 for 10 weeks. After 10-week treatment, compared with SHR model group, the levels of CYP2C11 mRNA and protein in heart, liver, kidney and aorta of 50 mg·kg^-1 atorvastatin group and in heart, kidney and aorta of 10 mg·kg^-1 atorvastatin group were markedly higher, but those in heart, kidney and aorta of WKY group were significantly lower. Urinary DHET excretion in all SHR groups was much higher than that in WKY group before experiment, after 10-week treatment, that in SHR model group was lower than that in 50 mg·kg^-1 atorvastatin group. Plasma lipids in 50 and 10 mg·kg^-1 atorvastatin groups were markedly lower than those in SHR model group. CONCLUSION Atorvastatin can significantly up-regulate the expression of CYP2C11 mRNA and protein and increase the production of epoxyeicosatrienoic acids in SHR, which may be one of the mechanisms of statins regulating hypertension.