Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
Cardiovasc Drugs Ther. 2021 Jun;35(3):587-598. doi: 10.1007/s10557-020-07002-z.
Atrial fibrillation (AF) is the most common type of arrhythmia. Atrial remodeling is a major factor to the AF substrate. The purpose of the study is to explore whether aliskiren (ALS) has a cardioprotective effect and its potential molecular mechanisms on atrial remodeling.
In acute experiments, dogs were randomly assigned to Sham, Paced and Paced+aliskiren (10 mg kg) (Paced+ALS) groups, with 7 dogs in each group. Rapid atrial pacing (RAP) was maintained at 600 bpm for 2 h for paced and Paced+ALS groups and atrial effective refractory periods (AERPs), inducibility of AF (AFi) and average duration time (ADT) were measured. In chronic experiments, there were 5 groups: Sham, Sham+ALS, Paced, Paced+ALS and Paced+ALS+PI3K antagonist wortmannin (WM) (70 μg kg day). RAP at 500 beats/min was maintained for 2 weeks. Inflammation and oxidative stress indicators were measured by ELISA assay, echocardiogram and pathology were used to assess atrial structural remodeling, phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/Akt) signaling pathways were studied by RT-PCR and western blotting to evaluate whether the cardioprotective effect of ALS works through PI3K/Akt signaling pathway.
The electrophysiological changes were observed after 2-h pacing. The AERP shortened with increased AFi and ADT, which was attenuated by ALS (P < 0.05). After pacing for 2 weeks, oxidative stress and inflammation markers in the Paced group were significantly higher than those in the Sham group (P < 0.01) and were reduced by ALS treatment (P < 0.01). The reduced level of antioxidant enzymes caused by RAP was also found to be elevated in ALS-treated group (P < 0.01). The results of pathology and echocardiography showed that RAP can cause atrial enlargement, fibrosis (P < 0.01), and were attenuated in ALS treatment group. The PI3K/Akt signaling pathway were downregulated induced by RAP. ALS could upregulate the PI3K/Akt pathway expression (P < 0.05). Furthermore, the cardioprotective effects in structural remodeling of ALS were suppressed by WM.
ALS may offer cardioprotection in RAP-induced atrial remodeling, which may partly be ascribed to its anti-inflammatory and anti-oxidative stress action and the regulation of PI3K/Akt signaling pathway.
心房颤动（AF）是最常见的心律失常类型。心房重构是 AF 基质的主要因素。本研究旨在探讨阿利克仑（ALS）是否对心房重构具有心脏保护作用及其潜在的分子机制。
在急性实验中，狗被随机分为 Sham、起搏和起搏+阿利克仑（10mg/kg）（起搏+ALS）组，每组 7 只。起搏+ALS 组和起搏组以 600bpm 的速度维持快速心房起搏（RAP）2h，测量心房有效不应期（AERP）、AFi 和平均持续时间（ADT）的可诱导性。在慢性实验中，共分为 5 组：Sham、Sham+ALS、起搏、起搏+ALS 和起搏+ALS+PI3K 拮抗剂渥曼青霉素（WM）（70μg/kg/天）。以 500 次/分的频率维持 RAP 2 周。通过 ELISA 测定炎症和氧化应激指标，超声心动图和病理学评估心房结构重构，通过 RT-PCR 和 Western blot 研究磷脂酰肌醇 3-羟激酶/蛋白激酶 B（PI3K/Akt）信号通路，评估 ALS 通过 PI3K/Akt 信号通路发挥心脏保护作用的能力。
起搏 2h 后观察到电生理变化。AERP 缩短，AFi 和 ADT 增加，ALS 可减轻这种变化（P<0.05）。起搏 2 周后，起搏组的氧化应激和炎症标志物明显高于 Sham 组（P<0.01），而 ALS 治疗组降低（P<0.01）。RAP 引起的抗氧化酶水平降低也发现可在 ALS 治疗组中升高（P<0.01）。病理学和超声心动图结果表明，RAP 可导致心房扩大、纤维化（P<0.01），而 ALS 治疗组可减轻这种变化。RAP 可下调 PI3K/Akt 信号通路。ALS 可上调 PI3K/Akt 通路表达（P<0.05）。此外，WM 抑制了 ALS 在结构重构中的心脏保护作用。
ALS 可能对 RAP 诱导的心房重构具有心脏保护作用，这可能部分归因于其抗炎和抗氧化应激作用以及对 PI3K/Akt 信号通路的调节。
