Wnt-C59 Attenuates Pressure Overload-Induced Cardiac Hypertrophy via Interruption of Wnt Pathway

Zhao, Zhengbo; Liu, Han; Yu, Li; Tian, Jingxiu; Deng, Songbai

doi:10.12659/msm.923025

Cited by 10 publications

(8 citation statements)

References 40 publications

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“…It has been shown to suppress the proliferation of intestinal stem cells and inhibit tumour growth 25 26. A recent study has reported that WNT-C59 attenuates pressure overload-induced cardiac hypertrophy 27. In this study, WNT-C59 significantly ameliorated both in vivo and in vitro DCM phenotypes, thus suggesting immediate translational potential.…”

Section: Discussionsupporting

confidence: 57%

Association between SCN5A R225Q variant and dilated cardiomyopathy: potential role of intracellular pH and WNT/β-catenin pathway

Yang

Zhao

et al. 2022

J Med Genet

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BackgroundThe SCN5A variant is a common cause of familial dilated cardiomyopathy (DCM). We previously reported a SCN5A variant (c.674G>A), located in the high-risk S4 segment of domain I (DI-S4) region in patients with idiopathic DCM and R225Q knockin (p.R225Q) mice carrying the c.674G>A variant exhibited prolonged baseline PR intervals without DCM phenotypes. In this study, we explored the association and mechanism between R225Q variant and DCM phenotype.MethodsPrevalence of DI-S4 variant was compared between patients with idiopathic DCM and the control participants. R225Q knockin and wild-type (WT) mice were subjected to doxorubicin (DOX), D-galactose (D-gal) or D-gal combined with DOX.ResultsClinical data suggested that the prevalence of DI-S4 variant was higher in DCM group than in the control group (4/90 (4.4%) vs 3/1339 (0.2%), p<0.001). Cardiomyocytes from R225Q knockin mice treated with D-gal and DOX exhibited more significant hypertrophic phenotype and weaker contraction/dilation function and an increased level of apoptosis as compared with WT mice. Mechanistically, we found that R225Q variant could increase intracellular pH and further induce the activation of the WNT/β-catenin pathway as well as the overexpression of pro-hypertrophic and pro-apoptotic targets. WNT-C59 inhibitor improved cardiac function in the R225Q knockin mice treated with D-gal and DOX.ConclusionOur results suggest that R225Q variant is associated with increased susceptibility to DCM. Ageing could enhance this process via activating WNT/β-catenin signaling in response to increased intracellular pH. Antagonising the WNT/β-catenin pathway might be a potential therapeutic strategy for mitigating R225Q variant-related DCM pathogenesis.

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Section: Discussionsupporting

confidence: 57%

Association between SCN5A R225Q variant and dilated cardiomyopathy: potential role of intracellular pH and WNT/β-catenin pathway

Yang

Zhao

et al. 2022

J Med Genet

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“…Conversely, inhibitors of Wnt signalling limit fibrosis. For example, Wnt-C59, which inhibits porcupine to block Wnt secretion, attenuates renal and cardiac fibrosis [ 24 , 25 ]. Small-molecule inhibitors of FZD8 have been shown to inhibit ECM gene expression [ 26–28 ].…”

Section: Introductionmentioning

confidence: 99%

Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease

et al. 2022

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Intestinal fibrosis and stricture formation is an aggressive complication of Crohns disease (CD), linked to increased morbidity and costs. This study investigates the contribution of Wnt signalling to intestinal fibrogenesis, considers potential crosstalk between Wnt and TGFβ signalling pathways and assesses the therapeutic potential of small-molecule Wnt inhibitors.β-catenin expression was explored by immunohistochemistry in FFPE tissue from patient-matched non-strictured (NSCD) and strictured (SCD) intestine (n=6 pairs). Functional interactions between Wnt activation, TGFβ signalling and Collagen-I expression were explored in CCD-18Co cells and primary CD myofibroblast cultures established from surgical resection specimens (n=16) using small molecule Wnt inhibitors and molecular techniques, including siRNA-mediated gene knockdown, immunofluorescence, Wnt gene expression arrays and western blotting. Fibrotic SCD tissue was marked by an increase in β-catenin positive cells. In vitro, activation of Wnt-β-catenin signalling increased Collagen-I expression in CCD-18Co cells. Conversely, ICG-001, an inhibitor of β-catenin signalling, reduced Collagen-I expression in cell lines and primary CD myofibroblasts. TGFβ increased β-catenin protein levels but did not activate canonical Wnt signalling. Rather, TGFβ up-regulated WNT5B, a non-canonical Wnt ligand, and the Wnt receptor FZD8, which contributed directly to the up-regulation of Collagen-I through a β-catenin-independent mechanism. Treatment of CCD-18Co fibroblasts and patient-derived myofibroblasts with the FZD8 inhibitor 3235-0367 reduced extracellular matrix expression. Our data highlight small-molecule Wnt inhibitors of both canonical and non-canonical Wnt signalling, as potential anti-fibrotic drugs to treat SCD intestinal fibrosis. They also highlight the importance of the crosstalk between Wnt and TGFβ signalling pathways in CD intestinal fibrosis.

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“…Although the role of the Wnt signaling pathway in CRA-induced VI has not yet been reported, studies have shown that β-catenin-mediated Wnt signaling plays a critical role in cardiac hypertrophy [ 61 ], vascular calcification [ 62 ], arterial stiffness [ 63 ], and angiogenesis [ 64 ]. We have determined the expression of 5 indicators related to the Wnt signaling pathway; however, the mechanism underlying the involvement of the Wnt signaling pathway in CRA-induced VI remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Proteomics-based evaluation of the mechanism underlying vascular injury via DNA interstrand crosslinks, glutathione perturbation, mitogen-activated protein kinase, and Wnt and ErbB signaling pathways induced by crotonaldehyde

Xie

Gao

et al. 2022

Clin Proteom

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Crotonaldehyde (CRA)—one of the major environmental pollutants from tobacco smoke and industrial pollution—is associated with vascular injury (VI). We used proteomics to systematically characterize the presently unclear molecular mechanism of VI and to identify new related targets or signaling pathways after exposure to CRA. Cell survival assays were used to assess DNA damage, whereas oxidative stress was determined using colorimetric assays and by quantitative fluorescence study; additionally, cyclooxygenase-2, mitogen-activated protein kinase pathways, Wnt3a, β-catenin, phospho-ErbB2, and phospho-ErbB4 were assessed using ELISA. Proteins were quantitated via tandem mass tag-based liquid chromatography-mass spectrometry and bioinformatics analyses, and 34 differentially expressed proteins were confirmed using parallel reaction monitoring, which were defined as new indicators related to the mechanism underlying DNA damage; glutathione perturbation; mitogen-activated protein kinase; and the Wnt and ErbB signaling pathways in VI based on Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein–protein interaction network analyses. Parallel reaction monitoring confirmed significant (p < 0.05) upregulation (> 1.5-fold change) of 23 proteins and downregulation (< 0.667-fold change) of 11. The mechanisms of DNA interstrand crosslinks; glutathione perturbation; mitogen-activated protein kinase; cyclooxygenase-2; and the Wnt and ErbB signaling pathways may contribute to VI through their roles in DNA damage, oxidative stress, inflammation, vascular dysfunction, endothelial dysfunction, vascular remodeling, coagulation cascade, and the newly determined signaling pathways. Moreover, the Wnt and ErbB signaling pathways were identified as new disease pathways involved in VI. Taken together, the elucidated underlying mechanisms may help broaden existing understanding of the molecular mechanisms of VI induced by CRA.

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Wnt-C59 Attenuates Pressure Overload-Induced Cardiac Hypertrophy via Interruption of Wnt Pathway

Cited by 10 publications

References 40 publications

Association between SCN5A R225Q variant and dilated cardiomyopathy: potential role of intracellular pH and WNT/β-catenin pathway

Association between SCN5A R225Q variant and dilated cardiomyopathy: potential role of intracellular pH and WNT/β-catenin pathway

Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease

Proteomics-based evaluation of the mechanism underlying vascular injury via DNA interstrand crosslinks, glutathione perturbation, mitogen-activated protein kinase, and Wnt and ErbB signaling pathways induced by crotonaldehyde

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