β1受体反义基因治疗对肾性高血压大鼠心脏的保护作用

目的: 探讨阳离子脂质体混合物介导的β₁受体反义基因对肾性高血压大鼠血压和心脏的影响及机制。方法: 将24只雄性SD大鼠随机分成4组(n=6):两肾一夹模型组(2K1C组),两肾一夹模型+反义核苷酸组(尾静脉β₁-AS-ODN 0.5 mg·kg^-1,反义组),两肾一央模型+反向核苷酸组(尾静脉β₁-IN-ODN 0.5 mg·kg^-1,反 向组),假手术组。常规方法测定尾动脉收缩压、左室血流动力学指标及左心室重量指数(LVMI),以光镜观察心肌组织变化,免疫组织化学方法检测心肌Bcl-2、 Bax的表达。结果: 单剂反义寡核苷酸治疗可持续降压27 d,血压最低可降至120 mmHg左右;并可明显改善左室收缩、舒张功能;反义组的左室重量指数也显著低于2K1C组(P<0.01);心肌细胞病理变化也较2K1C 组改善;2K1C组心肌Bcl-2/Bax比值明显低于假手术组,而反义组与2K1C组相比,Bcl-2/Bax比值明显升高 (P<0.05)。结论: 以β受体为靶基因的反义基因单剂治疗在有效而持久的控制肾性高血压的同时,可显著逆转左室肥厚,改善左室功能,其机制可能与升高Bcl-2/Bax比值、抑制心肌细胞凋亡相关。说明β受体反义基因治疗对肾性高血压大鼠具有心脏保护作用。

Protection effect of β1 receptor mRNA antisense inhibition on heart of renal hypertensive rats

AIM: To explore the effect and mechanism on blood pressure and heart protection of renal hypertension in rats treated with β₁ receptor antisense oli-godeoxynucleotides (β₁-AS-ODN) by delivery with cation-icliposomes DOTAP/DOPE.METHODS: 24 SD rats were divided randomly into 4 groups of 6 each group two groups of 2KIC rats were treated via tail vein injection with β₁-AS-ODN or inverted oli gonucleotides against rat β₁-AR MNA (β₁-IN-ODN) of 0.5 mg·kg^-1 once. 6 unltreated 2K1C rats and shamed rats served as positive andnormal controls. Blood pressure (BP), cardiac haemodynamics, and left ventricular index (LVW/BW) were measured. The histological changes of myocardium were observed by optical microscope and the expressions of Bcl-2 and Bax in myocardium were examined by immunohistochemical method.RESULTS: The single dose management of β₁-AS-ODN decreased blood pressure to 120 mm-Hg for 27 days and improved the LV function obviously P < 0.01). The value of LVW/BW in β₁-AS-ODN oup is much less than the value of that in 2K1C group(P 0.01). Compared with that of 2K1C group, thethological changes of myocardium inβ₁-AS-ODN groupmeliorated. The radio of bcl-2/Bax in 2KIC group wasless than sham group, and the radio of that in β₁-AS-ODN group was more than 2KIC group (P < 0. 05).CONCLUSION: β₁ receptor antisense oligodeoxynucleotidescan maintain anti-hypertension effect for atime and improve LV function, effectively reverses left ventricular hypertrophy in 2K1C renal hypertensive rats. The mecha-nism of which may be related to the suppressing of cell apoptosis of myocardium by increasing Bcl-2/Bax. It sug-gests that, receptor mRNA antisense had the heart protection effect in renal hypertensive raf.