Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis

Methatham, Thanachai; Tomida, Shota; Kimura, Natsuka; Imai, Yasushi; Aizawa, Kenichi

doi:10.1038/s41598-021-94169-6

Cited by 23 publications

(12 citation statements)

References 64 publications

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“…This finding indicated that inhibition of Ang II-induced Wnt activation was related to KDM5B knockdown. In recent years, increasing studies have demonstrated that the Wnt-related pathway contributed to tissue fibrosis − and worked together with the TGF-β pathway. , Therefore, we focused on the Wnt-related pathway in the following study.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Pyrazole-Based KDM5B Inhibitor TK-129 and Its Protective Effects on Myocardial Remodeling and Fibrosis

Tang

Jiao

et al. 2022

J. Med. Chem.

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Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 μM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis.

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Section: Resultsmentioning

confidence: 99%

Discovery of Novel Pyrazole-Based KDM5B Inhibitor TK-129 and Its Protective Effects on Myocardial Remodeling and Fibrosis

Tang

Jiao

et al. 2022

J. Med. Chem.

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“…One study showed that up-regulated miR-128 mediated heart injury by activating wnt signaling pathway in HF mice [28]. Another study showed that inhibition of the canonical wnt signaling pathway prevents HF by ameliorating cardiac hypertrophy and brosis [29]. And transcription factor 7-like 2 mediates canonical Wnt/β-catenin signaling in HF [30].…”

Section: Discussionmentioning

confidence: 99%

Identification of signature genes and functional genetic variants in heart failure by integrated bioinformatics analysis

Dai

Zhang

et al. 2023

Preprint

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Heart failure (HF) is a syndrome which the heart fails to meet the metabolic needs of the tissues and affects millions of people all over the world, bringing a great burden to families and society. Studies have shown that genetic factors play an important role in the occurrence and development of HF, but the genetic molecular mechanisms of HF remain to be explored. In our study, the bioinformatics methods were used in combination, the microarray datasets of GSE57338, GSE76701 were retrieved from the gene expression comprehensive database. After merging the above two microarray data and adjusting batch effects, differentially expressed genes (DEG) were determined. Functional enrichment analysis was performed based on Gene Ontology (GO) resources, Kyoto Encyclopedia of Genes and Genomes (KEGG) resources, gene set enrichment analysis (GSEA). Protein protein interaction (PPI) network was constructed using string database. Combined with the above important bioinformatics information, the potential key genes were selected. We identified 181 patients with HF and 140 normal controls (NC). There were 408 DEGs among HF samples, including 224 up-regulated genes and 184 down-regulated genes. The GO and KEGG enrichment analysis revealed the molecular mechanism of HF. GSEA enrichment analysis showed that most DEGs were significantly enriched in wnt signal pathway, histidine metabolism, beta alanine metabolism and so on. PPI networks showed that target genes CXCL10, DDX60, HERC6, IFI44L, IFIT1, IFIT2, IFIT3, MX1, RSAD2, XAF1 are expected to become new targets for HF. The eQTL analysis showed that the hub genes DDX60, HERC6, IFI44L, IFIT1, IFIT2, IFIT3, MX1, RSAD2, XAF1 are regulated by the eight genetic variations of single nucleotide polymorphisms, including rs55730499, rs140570886, rs600038, rs740363, rs1520832, rs10812610, rs6473383 and rs563519. Our findings provide potential biomarkers or therapeutic targets that are genetically regulated for the further study of HF, which contribute to the development of advanced prediction, diagnosis and treatment strategies.

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“…Persistent activation of endothelial Wnt/β-catenin signaling induces HF ( 30 ). Besides, cardiac fibroblasts are the main cell types in cardiac fibrosis ( 31 ); interestingly, Wnt/β-catenin signaling also had vital functions in regulating fibroblast activation and ECM gene expressions ( 32 ). Thus, studying the Wnt/β-catenin pathway is the key to unveiling the pathogenesis in HF.…”

Section: Discussionmentioning

confidence: 99%

Expression of connexin 43 protein in cardiomyocytes of heart failure mouse model

Liu

Yang

Zhao

et al. 2022

Front. Cardiovasc. Med.

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Heart failure (HF) is the end stage of various cardiovascular diseases, with high morbidity and mortality, and is associated with a poor prognosis. One of the primary causes of HF is aortic valve disease, manifested by progressive aortic valve stenosis (AVS), resulting in increased left ventricular load, ventricular hypertrophy, ultimately ventricular dysfunction, and HF. Early assessment of the degree of cardiomyopathy and timely intervention is expected to improve patients’ cardiac function and delay or even avoid the occurrence of HF. The Wnt signaling pathway is mainly involved in regulating myocardial insufficiency after valve stenosis. Connexin 43 protein (Cx43) is an essential target of Wnt signaling pathway that forms gap junction (GJ) structures and is widely distributed in various organs and tissues, especially in the heart. The distribution and transformation of Cx43 among cardiac cells are crucial for the development of HF. To specifically label Cx43 in vivo, we established a new Cx43-BFP-GFP mouse model with two loxp sites on both sides of the tag BFP-polyA box, which can be removed by Cre recombination. This double-reporter line endowed us with a powerful genetic tool for determining the area, spatial distribution, and functional status of Cx43. It also indicated changes in electrical conduction between cells in a steady or diseased state.

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Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis

Cited by 23 publications

References 64 publications

Discovery of Novel Pyrazole-Based KDM5B Inhibitor TK-129 and Its Protective Effects on Myocardial Remodeling and Fibrosis

Discovery of Novel Pyrazole-Based KDM5B Inhibitor TK-129 and Its Protective Effects on Myocardial Remodeling and Fibrosis

Identification of signature genes and functional genetic variants in heart failure by integrated bioinformatics analysis

Expression of connexin 43 protein in cardiomyocytes of heart failure mouse model

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