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Attenuation of atrial remodeling by aliskiren via affecting oxidative stress, inflammation and PI3K/Akt signaling pathway

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Abstract

Introduction

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.

Methods

In acute experiments, dogs were randomly assigned to Sham, Paced and Paced+aliskiren (10 mg kg−1) (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−1 day−1). 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.

Results

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.

Conclusions

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.

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Acknowledgments

The authors would like to express their special thanks to Beth Gabris in the Department of Medicine, Heart and Vascular Institute, University of Pittsburgh, USA, for her great help in editing the English language of the manuscript.

Funding

This study was funded by the Program of Natural Science Foundation of China (grant number 81370300), the China Education Ministry Colleges and Universities Special Scientific Research Foundation for Doctoral Advisor Class (grant number 20121202110004), the Tianjin Natural Science Foundation (grant number 17JCQNJC11400) and the Key Laboratory Science Foundation of Second Hospital of Tianjin Medical University (grant number 2017ZDSYS05).

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Authors and Affiliations

  1. 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

    Zhiqiang Zhao, Ruiling Li, Xinghua Wang, Jian Li, Meng Yuan, Enzhao Liu, Tong Liu & Guangping Li

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  1. Zhiqiang Zhao
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Correspondence to Guangping Li.

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Zhao, Z., Li, R., Wang, X. et al. Attenuation of atrial remodeling by aliskiren via affecting oxidative stress, inflammation and PI3K/Akt signaling pathway. Cardiovasc Drugs Ther 35, 587–598 (2021). https://doi.org/10.1007/s10557-020-07002-z

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