β_1受体反义基因治疗对肾性高血压大鼠心脏的保护作用

Protection effect of β_1 receptor mRNA antisense inhibition on heart of renal hypertensive rats

目的：探讨阳离子脂质体混合物介导的β_1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β_1-AS-ODN 0．5 mg·kg^(-1)，反义组)，两肾一夹模型+反向核苷酸组(尾静脉β_1-IN-ODN 0．5mg·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27d，血压最低可降至120mmHg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_1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_1受体反义基因治疗对肾性高血压大鼠具有心脏保护作用。

AIM： To explore the effect and mechanism on blood pressure and heart protection of renal hypertension in rats treated with β1 receptor antisense oligodeoxynucleotides （β1-AS-ODN） by delivery with cationic liposomes DOTAP/DOPE. METHODS： 24 SD rats were divided randomly into 4 groups of 6 each group： two groups of 2K1C rats were treated via tail vein injection with β1-AS-ODN or inverted oligonucleotides against rat β1-AR mRNA （β1-IN-ODN） of 0.5 mg·kg^-1 once. 6 untreated 2K1C rots and shamed rats served as positive and normal 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 131-AS-ODN decreased blood pressure to 120 mmHg for 27 days and improved the LV function obviously （P 〈 0.01）. The value of LVW/BW in β1-AS-ODN group is much less than the value of that in 2K1C group （P 〈 0.01）. Compared with that of 2K1C group, the pathological changes of myocardium in β1-AS-ODN group meliorated. The radio of bcl-2/Bax in 2K1C group was less than sham group, and the radio of that in β1-AS-ODN group was more than 2K1C group （P 〈 0.05）. CONCLUSION： β1 receptor antisense oligodeoxynucleotides can maintain anti-hypertension effect for a long time and improve LV function, effectively reverses left ventricular hypertrophy in 2K1C renal hypertensive rats. The mechanism of which may be related to the suppressing of cell apoptosis of myocardium by increasing Bcl-2/Bax. It suggests that β1 receptor mRNA antisense had the heart protection effect in renal hypertensive rats.