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Front. Physiol. | doi: 10.3389/fphys.2019.00597

Time series gene expression profiling and temporal regulatory pathway analysis of Angiotensin II induced atrial fibrillation in mice

  • 1Dalian Medical University, China
  • 2Dalian University, China

Background/Aims: Angiotensin II (Ang II) and hypertension play critical roles in the pathogenesis of the atrial remodeling that contributes to atrial fibrillation (AF). However, the gene expression profiles and signaling pathways in atria during the development of AF induced by Ang II remain unknown. Methods: Wild-type male mice (C57BL/6 background, 10 weeks old) were administered an infusion of Ang II (2000 ng/kg/min) using an osmotic pump for 1, 2, and 3 weeks. Blood pressure was measured by the tail-cuff method. AF was induced and recorded. Atrial enlargement and remodeling were examined by echocardiography and Masson’s trichrome staining. Time-series microarray analyses were conducted to examine gene expression profiles and pathways. Results: Ang II infusion resulted in marked elevation of systolic blood pressure, increased AF incidence and duration, atrial enlargement, fibrosis, and atrial infiltration of myofibroblasts and F4/80-positive macrophages in a time-dependent manner. Microarray results showed that 1,719 genes were differentially expressed in the atrium at weeks 1, 2, and 3 after Ang II infusion. Gene ontology showed that these genes participate mainly in immune system processes, and regulation of cell migration, cell adhesion, complement activation, and the inflammatory response. Significant pathways included lysosomal and phagosomal pathways, which are involved in antigen processing and presentation, as well as chemokine signaling, and extracellular matrix–receptor interaction, which are known to play important roles in Ang II-induced AF. Moreover, these differentially expressed genes were classified into 50 profiles by hierarchical cluster analysis. Of these, eight profiles were significant and contained a total of 1,157 genes. Gene co-expression network analysis identified that Pik3cg (also known as phosphoinositide-3-kinase regulatory subunit 3) was localized in the core of the gene network, and was the most highly expressed among the Pik3 isoforms at different time points. Conclusions: The present findings revealed that many genes are involved in Ang II-induced AF, and highlighted that Pik3cg may play a central role in this disease.

Keywords: Angiotensin II, Atrial Fibrillation, Microarray, Time series gene expression profiling, PIK3CG

Received: 26 Jan 2019; Accepted: 26 Apr 2019.

Edited by:

Esther Pueyo, University of Zaragoza, Spain

Reviewed by:

Diego Franco, Universidad de Jaén, Spain
Fabian S. Gomar, University of Valencia, Spain
Jizhong Cheng, Baylor College of Medicine, United States  

Copyright: © 2019 Li, Wu, Han, Chen, Zou, Dong and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Hui-Hua Li, Dalian Medical University, Dalian, China, hhli1935@aliyun.com