Time Series Gene Expression Profiling and Temporal Regulatory Pathway Analysis of Angiotensin II Induced Atrial Fibrillation in Mice

Abstract

Background/Aim: 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 (BP) 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 BP, 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. Conclusion: 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.

Angiotensin II Stimulates the Proliferation and Migration of Lymphatic Endothelial Cells Through Angiotensin Type 1 Receptors

“…Lymphatic remodeling is a major feature of lymphatic diseases and involves alterations in the proliferation, migration and apoptosis of LECs. Ang II is known to bind AT1R to activate these signaling pathways, which are the primary mechanisms involved in Ang II-induced inflammation, fibrosis, and oxidative stress in various tissues and cells (Dang et al, 2015;Zhang et al, 2018;Wu et al, 2019). In the present study, we extended these findings and further reveled that Ang II infusion significantly promotes cardiac lymphangiogenesis (Figure 1), but whether this effect is direct or indirect remains unclear.…”

“…The fold change in gene expression of Ang II-treated cells for every time point was normalized to the control group. Hierarchical clustering (visualized with a heatmap), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, global signal transduction network, co-expression network and gene expression trend bioinformatics analyses were performed as previously described (Wu et al, 2019). Statistical analyses of microarray and bioinformatics data were performed with Fisher's exact test and Duncan's multiple range test to calculate the P-value and FDR.…”

Bioinformatic analysis for the identification of potential gene interactions and therapeutic targets in atrial fibrillation

“…In GO molecular function analysis, cell adhesion molecule binding was the most significantly enriched molecular function. Similar to cell migration, cell adhesion has also been reported to be related to atrial fibrillation [16].…”

“…The GO biological process enrichment analysis showed that positive cell migration was the most significantly enriched biological process. The regulation of cell migration has been proven to be related to atrial fibrillation occurrence and maintenance [16]. It has been reported that inhibition of fibroblast migration may attenuate atrial fibrosis and reduce AF vulnerability [17].…”

Effects of Isorhamnetin in Human Amniotic Epithelial Stem Cells in vitro and Its Cardioprotective Effects in vivo

“…Osmotic pumps are designed to continuously deliver compounds to small animals at a constant rate. This technique is commonly used to induce AF, aortic aneurysm, and hypertension, leading to serious heart disease or sudden death (Wu et al, 2019). AgII 1,000 ng/kg/min is commonly used.…”