Selective blocking of CXCR2 prevents and reverses atrial fibrillation in spontaneously hypertensive rats

Zhang, Yun-Long; Teng, Fei; Han, Xiao; Li, Pang-Bo; Yan, Xiao; Guo, Shubin; Li, Huihua

doi:10.1111/jcmm.15694

Cited by 20 publications

(26 citation statements)

References 28 publications

(92 reference statements)

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“…For example, Zhang et al (2020a) provided evidence that the expression level of CXCR2 and the number of CXCR2+ immune cells were markedly increased in the atria of angiotensin (Ang) II-infusion-induced AF models. The administration of CXCR2 inhibitor SB225002 or knockout of CXCR2 significantly reduced AF inducibility, duration, conduction abnormalities and atrial fibrosis in mice compared with the vehicle treatment (Zhang et al 2020a(Zhang et al , 2020b. Fan and Wei (2020) and Zou et al (2019) also identified upregulated CXCR2 as a hub node for AF patients after the PPI network analysis of the GSE79768 dataset.…”

Section: Discussionmentioning

confidence: 95%

Identification of atrial fibrillation-associated lncRNAs and exploration of their functions based on WGCNA and ceRNA network analyses

Liu¹,

Liang²,

Wang³

et al. 2021

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Atrial fibrillation (AF) is a common cardiac arrhythmia that induces serious complications. However, pharmacological treatments of AF remain challenging. This study aimed to screen crucial long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNA (mRNAs) for AF using the microarray datasets (lncRNAs and mRNAs: GSE79768, GSE115574; miRNAs: GSE68475) collected from the Gene Expression Omnibus database. Weighted correlation network analysis of GSE79768 and GSE115574 datasets identified five modules were highly related to AF status. Among 118 module-related differentially expressed mRNAs, FBXW7, EGFR, CXCR2, ROCK1 and UBE2D1 were considered as hub genes according to the gene significance, module membership and the topological characteristics for the nodes in the protein-protein interaction network. lncRNA MIR100HG and LINC01105 may function by co-expressing with (MIR100HG-ROCK1/FBXW7/UBE2D1, LINC01105-EGFR) mRNAs or sponging miRNAs to regulate mRNAs (LINC01105-miR-125a-3p-EGFR, MIR100HG-miR-200b-3p-FBXW7, MIR100HG-miR-561-3p-CXCR2, MIR100HG-miR-548z-UBE2D1). Connectivity Map and Comparative Toxicogenomics Database searches predicted dexamethasone may treat AF by reversing the expression of MIR100HG; artemisinin may reverse the expression of hub DEGs. In conclusion, our results may provide novel molecular mechanisms and potential therapeutic targets and drugs for AF.

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Section: Discussionmentioning

confidence: 95%

Identification of atrial fibrillation-associated lncRNAs and exploration of their functions based on WGCNA and ceRNA network analyses

Liu¹,

Liang²,

Wang³

et al. 2021

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“…Recently, our microarray results discovered that chronic Ang II infusion induces mainly the activation of inflammatory chemokines, extracellular matrix-receptor interactions, and ubiquitin-proteasome system in the atrial tissue [ 7 ]. Indeed, the expression levels of several components of these signaling pathways, including CXCL1, CXCR2, and UCHL1, and the immunoproteasome catalytic subunits LMP10/PSMB10 and LMP7/PSMB8, are significantly upregulated in Ang II-infused atria and patients with atrial fibrillation, and play a critical role in the development of hypertensive atrial fibrillation in mice [ 7 , 11 , 12 , 20 , 21 ]. These previous data were further confirmed by time series analysis of proteome profiles in the same mouse model, and highlight that these genes are important regulators of atrial fibrillation development.…”

Section: Discussionmentioning

confidence: 99%

Time series proteome profile analysis reveals a protective role of citrate synthase in angiotensin II-induced atrial fibrillation

Teng

Han

et al. 2022

Journal of Hypertension

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Background: Angiotensin (Ang) II and elevated blood pressure are considered to be the main risk factors for atrial fibrillation. However, the proteome profiles and key mediators/signaling pathways involved in the development of Ang II-induced atrial fibrillation remain unclear.Methods: Male wild-type C57BL/6 mice (10-week old) were infused with Ang II (2000 ng/kg per min) for 1, 2, or 3 weeks, respectively. Time series proteome profiling of atrial tissues was performed using isobaric tags for relative and absolute quantitation and liquid chromatography coupled with tandem mass spectrometry.Results: We identified a total of 1566 differentially expressed proteins (DEPs) in the atrial tissues at weeks 1, 2, and 3 after Ang II infusion. These DEPs were predominantly involved in mitochondrial oxidation-reduction and tricarboxylic acid cycle in Ang II-infused atria. Moreover, coexpression network analysis revealed that citrate synthase, a rate-limiting enzyme in the tricarboxylic acid cycle, was localized at the center of the mitochondrial oxidationreduction process, and its expression was significantly downreguated in Ang II-infused atria at different time points. Cardiomyocyte-specific overexpresion of citrate synthase markedly reduced atrial fibrillation susceptibility and atrial remodeling in mice. These beneficial effects were associated with increased ATP production and mitochondrial oxidative phosphorylation system complexes I-V expression and inhibition of oxidative stress. Conclusion:The current study defines the dynamic changes of the DEPs involved in Ang II-induced atrial fibrillation, and identifies that citrate synthase plays a protective role in regulating atrial fibrillation development, and increased citrate synthase expression may represent a potential therapeutic option for atrial fibrillation treatment.

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“…Chemokines are a large family of small, inducible, secreted proteins that bind to coupled GPCRs on target cells and have the ability to recruit leukocytes to sites of injury, which contributes to AF development [ 39 – 42 ]. For example, Zhang et al found that CXCL1/CXCR2 signaling could drive the infiltration of monocyte in atria accelerating atrial remodeling and AF after hypertension [ 42 ], while these effects could be mitigated by inhibiting CXCR2 with SB225002 (ref [ 41 ].). CXCL12/CXCR4 axis also involves in a diversity of pathological processes, such as homeostatic immune cell migration, inflammatory response, tissue repair, and cell survival, which is considered as an attractive therapeutic target both in cardiac and noncardiac diseases.…”

Section: Discussionmentioning

confidence: 99%

CXCL12/CXCR4 axis as a key mediator in atrial fibrillation via bioinformatics analysis and functional identification

et al. 2021

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Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well understood. In this study, we sought to identify hub genes involved in AF, and explored their functions and underlying mechanisms based on bioinformatics analysis. Five microarray datasets in GEO were used to identify the differentially expressed genes (DEGs) by Robust Rank Aggregation (RRA), and hub genes were screened out using protein–protein interaction (PPI) network. AF model was established using a mixture of acetylcholine and calcium chloride (Ach-CaCl2) by tail vein injection. We totally got 35 robust DEGs that mainly involve in extracellular matrix formation, leukocyte transendothelial migration, and chemokine signaling pathway. Among these DEGs, we identified three hub genes involved in AF, of which CXCL12/CXCR4 axis significantly upregulated in AF patients stands out as one of the most potent targets for AF prevention, and its effect on AF pathogenesis and underlying mechanisms were investigated in vivo subsequently with the specific CXCR4 antagonist AMD3100 (6 mg/kg). Our results demonstrated an elevated transcription and translation of CXCL12/CXCR4 axis in AF patients and mice, accompanied with the anabatic atrial inflammation and fibrosis, thereby providing the substrate for AF maintenance. Blocking its signaling via AMD3100 administration in AF model mice reduced AF inducibility and duration, partly ascribed to decreased atrial inflammation and structural remodeling. Mechanistically, these effects were achieved by reducing the recruitment of CD3+ T lymphocytes and F4/80+ macrophages, and suppressing the hyperactivation of ERK1/2 and AKT/mTOR signaling in atria of AF model mice. In conclusion, this study provides new evidence that antagonizing CXCR4 prevents the development of AF, and suggests that CXCL12/CXCR4 axis may be a potential therapeutic target for AF.

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Selective blocking of CXCR2 prevents and reverses atrial fibrillation in spontaneously hypertensive rats

Cited by 20 publications

References 28 publications

Identification of atrial fibrillation-associated lncRNAs and exploration of their functions based on WGCNA and ceRNA network analyses

Identification of atrial fibrillation-associated lncRNAs and exploration of their functions based on WGCNA and ceRNA network analyses

Time series proteome profile analysis reveals a protective role of citrate synthase in angiotensin II-induced atrial fibrillation

CXCL12/CXCR4 axis as a key mediator in atrial fibrillation via bioinformatics analysis and functional identification

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