GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis

Jia, Wanwan; Wu, Weijun; Yang, Di; Xiao, Chenxi; Huang, Min; Long, Fen; Su, Zhenghua; Qin, Ming; Liu, Xinhua; Zhu, Yi‐Zhun

doi:10.1038/s41419-018-0570-5

Cited by 39 publications

(27 citation statements)

References 38 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is a positive feedback loop between the two (Leblond et al, 2017). Inhibition of angiogenesis has become a new choice for the treatment of RA in recent years (Jia et al, 2018). However, many drugs targeting RA angiogenesis are still under research and development (Alaarg et al, 2017;Feng and Chen, 2018), including Chinese medicine compounds or monomers.…”

Section: Discussionmentioning

confidence: 99%

Computational Prediction of Antiangiogenesis Synergistic Mechanisms of Total Saponins of Panax japonicus Against Rheumatoid Arthritis

Guo

Sreena

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

Objective: To investigate the anti-angiogenesis mechanisms and key targets of total saponins of Panax japonicus (TSPJ) in the treatment of rheumatoid arthritis (RA). Methods: RStudio3.6.1 software was used to obtain differentially expressed genes (DEGs) by analyzing the differences in gene expression in the synovial tissue of RA and to predict the potential targets of active compounds from TSPJ by the PharmMapper and SwissTargetPrediction databases. We evaluated the overlapping genes by intersectional analysis of DEGs and drug targets. Based on the overlapping genes, we used Cytoscape 3.7.2 software to construct a protein–protein interactions (PPI) network and applied Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to determine the mechanisms of the treatment. Finally, the correlations with angiogenesis-related genes were explored. Collagen-induced arthritis (CIA) model was established and treated with different doses of TSPJ. The manifestations of CIA were determined by evaluation of arthritis index and histology score. Serum levels of vascular endothelial growth factor (VEGF) and the hypoxia-inducible factor 1 (HIF-1) were tested by ELISA. The mRNA levels of IL-1β and IL-17A were detected by real time-quantitative PCR. Results : Altogether, 2670 DEGs were obtained by differential analysis, and 371 drug targets were predicted for four active components (Araloside A, Chikusetsusaponin IVa, Ginsenoside Rg2, and Ginsenoside Ro). A total of 52 overlapping genes were included in the PPI network and the KEGG analysis. However, only 41 genes in the PPI network had protein interactions. The results of the KEGG enrichment analysis were all related to angiogenesis, including VEGF and HIF-1 signaling pathways. Seven genes with negative correlations and 16 genes with positive correlations were obtained by correlational analysis of DEGs in the VEGF and HIF-1 signaling pathways. SRC proto-oncogene, nonreceptor tyrosine kinase (SRC), and the signal transducer and activator of transcription 3 (STAT 3) had a higher value of degree and showed a significant correlation in the pathways; they were regarded as key targets. Compared with the model group, TSPJ significantly relieved the symptoms and decreased the expression of VEGFA, HIF-1α, IL-1β, and IL-17A in serum or spleens of CIA mice. Conclusion: In the current study, we found that antiangiogenesis is one of the effective strategies of TSPJ against RA; SRC and STAT 3 may be the key targets of TSPJ acting on the VEGF and HIF-1 signaling pathways, which will provide new insight into the treatment of RA by inhibiting inflammation and angiogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Computational Prediction of Antiangiogenesis Synergistic Mechanisms of Total Saponins of Panax japonicus Against Rheumatoid Arthritis

Guo

Sreena

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Regulates Angiogenesis and Persistence of Inflammation (Jia et al, 2018b) MCP-1 Hypomethylation of the promoter region in atherosclerosis Increases the expression of MCP-1, promotes the recruitment of inflammatory cells (Liu et al, 2012) eNOS Hypermethylation of promoter region appears in pathological conditions…”

Section: Gata4mentioning

confidence: 99%

“…Moreover, evidence also points to potential roles for JMJD3 in vascular remodeling ( Luo et al, 2018 ) and in the regulation of the transcription factor GATA4. GATA4 functioning in inflammation persistence and angiogenesis in rheumatoid arthritis (RA) ( Jia et al, 2018 ).…”

Section: Do Epigenetics Mechanisms Contribute To Vascular Aging?mentioning

confidence: 99%

“…These observations suggesting that JMJD3 may represent a novel target for the development of new anti-inflammatory therapeutics for treating RA, the prevention and treatment of intima hyperplasia-related vascular diseases, and other pro-inflammatory conditions ( Liu et al, 2018 ; Jia et al, 2018a ; Luo et al, 2018 ; Wu et al, 2019 ). Likewise, the transcription factor GATA4, a key regulator of angiogenesis and persistence of inflammation in RA may also hold promise as a therapeutic target ( Jia et al, 2018 ). We also show that Fos-related antigen 1 (Fra-1) plays a novel and key role in promoting vascular aging by directly binding and activating the target proteins p21(WAF1/Cip1) and p16(INK4A) protein signaling systems.…”

Section: Epigenetics Regulation and Treatment Of Vascular Aging And Cmentioning

confidence: 99%

See 1 more Smart Citation

Epigenetics and Vascular Senescence–Potential New Therapeutic Targets?

et al. 2020

Self Cite

View full text Add to dashboard Cite

Epigenetics is defined as the heritable alterations of gene expression without changes to the coding sequence of DNA. These alterations are mediated by processes including DNA methylation, histone modifications, and non-coding RNAs mechanisms. Vascular aging consists of both structural and functional changes in the vasculature including pathological processes that drive progression such as vascular cell senescence, inflammation, oxidation stress, and calcification. As humans age, these pathological conditions gradually accumulate, driven by epigenetic alterations, and are linked to various aging-related diseases. The development of drugs targeting a spectrum of epigenetic processes therefore offers novel treatment strategies for the targeting of age-related diseases. In our previous studies, we identified HDAC4, JMJD3, Fra-1, and GATA4 as potential pharmacological targets for regulating vascular inflammation, injury, and senescence.

show abstract

“…LPS significantly induces the activation of GATA4 and leads to the development of myocardiac hypertrophy (Liu et al 2008). Recently, a study proposed that GATA4 played a global role in the inflammatory response by regulating the expression or release of inflammatory mediators in rheumatoid arthritis (Jia et al 2018). However, the role of GATA4 in the pathological process of dental pulpitis has been unclear.…”

Section: Gata4 In Pulpitismentioning

confidence: 99%

Lipopolysaccharide‐induced DNA damage response activates nuclear factor κB signalling pathway via GATA4 in dental pulp cells

et al. 2019

View full text Add to dashboard Cite

Aim To investigate the role of GATA‐binding protein 4 (GATA4) in the inflammatory response induced by DNA double‐strand breaks (DSBs) in human dental pulp cells (hDPCs). Methodology Lipopolysaccharide (LPS) was used for stimulating inflammation in dental pulp tissue in vivo and hDPCs in vitro. Expression levels of GATA4 and γ‐H2A.X (a marker for DSBs) were detected at different stages of pulpitis in a rat model and human pulp tissues by immunohistochemistry. Real‐time quantitative polymerase chain reaction and Western blot were performed to assess expression of GATA4 and γ‐H2A.X and the activation of nuclear factor κB (NF‐κB) in hDPCs stimulated by LPS. The comet assay was used for detecting the extent of DSBs in hDPCs. Immunocytochemistry and Western blot were utilized to evaluate expression of γ‐H2A.X and GATA4 and activation of NF‐κB in hDPCs pre‐treated with inhibitors of DNA damage response or transfected with GATA4 small interfering RNA before the treatment of LPS. Data were analysed statistically using one‐way anova or Kruskal–Wallis tests. Results The expression of GATA4 and activation of DNA damage response and NF‐κB in inflamed pulp tissue and LPS‐treated hDPCs were identified. Significantly decreased expression of GATA4 and significantly decreased inflammatory processes in hDPCs were demonstrated via suppression of DNA damage response (P < 0.05). In GATA4‐knockdown cells, the expression of γ‐H2A.X did not change, but nuclear translocation of p65 was significantly suppressed (P < 0.05) upon induction by LPS. Conclusions Lipopolysaccharide‐induced DSBs activated the NF‐κB signalling pathway in hDPCs, and GATA4 acts as a positive moderator of the progress. The involvement of GATA4 in this pathology may serve as a therapeutic target in pulpitis.

show abstract

GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis

Cited by 39 publications

References 38 publications

Computational Prediction of Antiangiogenesis Synergistic Mechanisms of Total Saponins of Panax japonicus Against Rheumatoid Arthritis

Computational Prediction of Antiangiogenesis Synergistic Mechanisms of Total Saponins of Panax japonicus Against Rheumatoid Arthritis

Epigenetics and Vascular Senescence–Potential New Therapeutic Targets?

Lipopolysaccharide‐induced DNA damage response activates nuclear factor κB signalling pathway via GATA4 in dental pulp cells

Contact Info

Product

Resources

About