聚乙二醇修饰载血管紧张素转化酶RNA壳聚糖纳米粒治疗高血压

Polyethylene glycol-modified chitosan nanoparticles loaded with angiotensin converting enzyme-sh RNA for hypertension

背景:临床治疗原发性高血压的传统降压药物一般半衰期较短,且治疗效果不佳。壳聚糖可以作为基因载体,将目标基因载入机体起到靶向治疗作用。聚乙二醇与DNA结合形成纳米粒后,可以起到表面保护效果,稳定纳米粒,使其在体内保持长循环。目的:探讨聚乙二醇修饰的载血管紧张素转化酶RNA壳聚糖纳米粒注射到自发性高血压模型大鼠体内后,对模型大鼠的降压疗效以及对心脏组织的影响。方法:实验共分为5组,取32只自发性高血压大鼠随机分为4组,为模型组、壳聚糖组、实验组、阳性药物组,每组8只;取8只正常大鼠,不作处理作为对照组。分组后分别于实验第1,10天进行给药2次,其中模型组和对照组尾静脉注射等量的生理盐水,壳聚糖组尾静脉注射1 mg/kg壳聚糖,实验组尾静脉注射1 mg/kg的聚乙二醇修饰载血管紧张素转化酶RNA壳聚糖纳米粒,阳性药物组灌胃0.5 mg/kg盐酸贝那普利。结果与结论:(1)血压水平:大鼠注射修饰的壳聚糖纳米粒后第3天,与第1天比血压显著下降(P<0.05);(2)组织学变化:实验组主动脉、肾脏及心脏组织切片显示均有绿色荧光表达,和血管紧张素转换酶的体内分布基本一致;(3)RT-PCR检测及左室功能检测:注射后第3天,与模型组相比,实验组各组织器管中血管紧张素转换酶m RNA表达水平及心肌肥厚相关指标减少(P<0.05)、心肌细胞肥大现象均有显著的减轻(P<0.05);(4)结果证实,聚乙二醇修饰的载血管紧张素转化酶RNA壳聚糖纳米粒可以降低高血压模型大鼠的血压值和修复受损心脏,其作用机制可能与血管紧张素转移酶有关。

BACKGROUND：Traditional antihypertensive drugs always have a short half-life period, and show unsatisfactory treatment outcomes. Chitosan, as a gene vector, can carry target genes into the designated location. Polyethylene glycol （PEG） combined with DNA to form the nanoparticles, which can provide surface protection, stabilize the nanoparticles and lengthen the nanoparticle’s half-life. OBJECTIVE：To investigate the antihypertensive effect and the histological changes of heart after PEG-modified chitosan nanoparticles loaded with angiotensin converting enzyme （ACE）-shRNA injected into the rat models of spontaneous hypertension. METHODS：There were five groups：32 rats with hypertension were randomized into model, chitosan experimental and positive drug groups （n=8 per group）;another 8 healthy rats served as controls. The rats in the model and control groups were given the injection of the same amount of normal saline via tail vein, the rats in the chitosan group received the injection of 1 mg/kg chitosan via the tail vein, those in the experiment group received the injection of 1 mg/kg PEG-modified chitosan nanoparticles loaded with ACE-shRNA, and the positive drug group rats were treated with 0.5 mg/kg benazepril hydrochloride via gastric lavage at 1 and 10 days, respectively. RESULTS AND CONCLUSION：The blood pressure in the experimental group at 3 days after treatment was significantly lower than that at 1 day （P〈0.05）. Aorta, renal and cardiac biopsies showed positive for green fluoresce in the experimental group, which was consistent with the in vivo distribution of ACE. At 3 days after treatment, compared with the model group, in the experimental group, ACE mRNA expression and levels of myocardial hypertrophy-related indicators were significantly decreased, and myocardial hypertrophy was significantly improved （P〈0.05）. These results revealed that PEG-modified ACE-shRNA chitosan nanoparticles can reduce the blood pressure and repair the injured heart of rat models of hypertension, which may be associated with ACE.