血管紧张素Ⅱ型（AT2）受体的激活可预防 Zucker 糖尿病肥胖大鼠的心肌肥厚。

Activation of angiotensin type 2 (AT2) receptors prevents myocardial hypertrophy in Zucker diabetic fatty rats.

机构信息

Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Via Cadore, 48, 20900, Monza, MB, Italy.

Dipartimento di Scienze Radiologiche, Oncologiche e Anatomopatologiche, Istituto di Anatomia Patologica, Sapienza Universita' di Roma, Rome, Italy.

出版信息

Acta Diabetol. 2019 Jan;56(1):97-104. doi: 10.1007/s00592-018-1220-1. Epub 2018 Sep 5.

DOI:10.1007/s00592-018-1220-1

PMID:30187136

Abstract

AIMS

Compound 21 (C21), selective AT2 receptor agonist, has cardioprotective effects in experimental models of hypertension and myocardial infarction. The aims of the study was to evaluate the effect of C21, losartan, or both in Zucker diabetic fatty (ZDF) rats (type 2 diabetes) on (1) the prevention of myocardial hypertrophy; (2) myocardial expression of phosphatase and tensin homolog (PTEN), a target gene of miR-30a-3p, involved in myocardial remodelling.

METHODS

Experiments were performed in ZDF (n = 33) and in control Lean (8) rats. From the 6th to the 20th week of age, we administered C21 (0.3 mg/kg/day) to 8 ZDF rats. 8 ZDF rats were treated with losartan (10 mg/kg/day), 8 rats underwent combination treatment, C21+ losartan, and 9 ZDF rats were left untreated. Blood glucose and blood pressure were measured every 4 weeks. At the end of the study the hearts were removed, the apex was cut for the quantification of PTEN mRNA and miR-30a-3p expression (realtime-PCR). Myocardial hypertrophy was evaluated by histomorphometric analysis, and nitrotyrosine expression (as marker of oxidative stress) by immunohistochemistry.

RESULTS

ZDF rats had higher blood glucose (p < 0.0001) with respect to control Lean rats, while blood pressure did not change. Both parameters were not modified by C21 treatment, while losartan and losartan + C21 reduced blood pressure in ZDF rats (p < 0.05). miR-30a-3p expression was increased in ZDF rats (p < 0.01) and PTEN mRNA expression was decreased (p < 0.05). ZDF rats developed myocardial hypertrophy (p < 0.01) and increased oxidative stress (p < 0.01), both were prevented by C21 or losartan, or combination treatment. C21 or losartan normalized the expression of miR-30a-3p and PTEN.

CONCLUSIONS

Activation of AT2 receptors or AT1 receptor blockade prevents the development of myocardial hypertrophy in ZDF rats. This occurs through the modulation of the miR-30a-3p/PTEN interaction.

摘要

目的

化合物 21（C21）是一种选择性的 AT2 受体激动剂，在高血压和心肌梗死的实验模型中具有心脏保护作用。本研究旨在评估 C21、氯沙坦或两者联合应用于（1）预防心肌肥厚；（2）磷酸酶和张力蛋白同源物（PTEN）在心肌重构中涉及的 miR-30a-3p 的靶基因在 Zucker 糖尿病肥胖（ZDF）大鼠（2 型糖尿病）中的表达。

方法

在 ZDF（n=33）和对照瘦（8）大鼠中进行实验。从第 6 周到第 20 周，我们给予 8 只 ZDF 大鼠 C21（0.3mg/kg/天）。8 只 ZDF 大鼠接受氯沙坦（10mg/kg/天）治疗，8 只大鼠联合治疗，C21+氯沙坦，9 只 ZDF 大鼠未接受治疗。每 4 周测量一次血糖和血压。研究结束时，取出心脏，切取心尖部用于定量检测 PTEN mRNA 和 miR-30a-3p 的表达（实时 PCR）。通过组织形态计量分析评估心肌肥厚，通过免疫组化检测硝基酪氨酸表达（作为氧化应激的标志物）。

结果

与对照瘦大鼠相比，ZDF 大鼠的血糖水平更高（p<0.0001），而血压没有变化。C21 治疗未改变这两个参数，而氯沙坦和氯沙坦+C21 降低了 ZDF 大鼠的血压（p<0.05）。miR-30a-3p 的表达在 ZDF 大鼠中增加（p<0.01），PTEN mRNA 的表达减少（p<0.05）。ZDF 大鼠发生心肌肥厚（p<0.01）和氧化应激增加（p<0.01），C21 或氯沙坦或联合治疗均可预防。C21 或氯沙坦可使 miR-30a-3p 和 PTEN 的表达正常化。