Downregulation of S100A4 Alleviates Cardiac Fibrosis via Wnt/β -Catenin Pathway in Mice

Li, Qian; Hong, Jian; Zhang, Yan‐Mei; Zhu, Mengyi; Wang, XinChun; Zhang, YanJuan; Chu, Ming; Yao, Jing; Xu, Di

doi:10.1159/000489683

Cited by 36 publications

(26 citation statements)

References 22 publications

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“…Together these results show that S100A4 overexpression led to a decreased activation of the fetal gene programm in our EHTs. Both findings, i.e., reduced steady state mRNA levels of mediators of fibrosis and hypertrophy are in line with recently reported data from Doroudgar and colleagues, who have shown more adverse fibrotic remodeling, more post-ischemic damage and increased Nppa and Nppb transcription in S100A4 KO mice (Doroudgar et al, 2016 ) and from Qian and colleagues, who have shown that siRNA-mediated downregulation of S100A4 alleviates cardiac fibrosis after LAD-ligation in mice (Qian et al, 2018 ).…”

Section: Discussionsupporting

confidence: 88%

S100A4 as a Target of the E3-Ligase Asb2β and Its Effect on Engineered Heart Tissue

et al. 2018

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Background: S100A4 has recently emerged as an important player in cardiac disease, affecting phenotype development in animal models of myocardial infarction and pathological cardiac hypertrophy, albeit it is unclear whether S100A4 exerts a detrimental or beneficial function. The goal of the current study was to analyze S100A4 expression in models of cardiac pathology, investigate its degradation by the ubiquitin-proteasome system (UPS), and furthermore examine the functional effects of S100A4 levels in a 3D model of engineered heart tissue (EHT).Methods and Results: S100A4 mRNA and protein levels were analyzed in different models of cardiac pathology via quantitative RT-PCR and Western blot, showing a higher S100A4 steady-state protein concentration in hearts of Mybpc3-knock-in (KI) hypertrophic cardiomyopathy (HCM) mice. COS-7 cells co-transfected with plasmids encoding mutant (MUT) Asb2β lacking the E3 ligase activity in combination with V5-tagged S100A4 plasmid presented higher S100A4-V5 protein steady-state concentrations than cells co-transfected with the Asb2β wild type (WT) plasmid. This effect was blunted by treatment with the specific proteasome inhibitor epoxomicin. Adeno-associated virus serotype 6 (AAV6)-mediated S100A4 overexpression in a 3D model of EHT did not affect contractile parameters. Immunofluorescence analysis showed a cytosolic and partly nuclear expression pattern of S100A4. Gene expression analysis in EHTs overexpressing S100A4-V5 showed markedly lower steady-state concentrations of genes involved in cardiac fibrosis and pathological cardiac hypertrophy.Conclusion: We showed that S100A4 protein level is higher in cardiac tissue of Mybpc3-KI HCM mice probably as a result of a lower degradation by the E3 ligase Asb2β. While an overexpression of S100A4 did not alter contractile parameters in EHTs, downstream gene expression analysis points toward modulation of signaling cascades involved in fibrosis and hypertrophy.

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Section: Discussionsupporting

confidence: 88%

S100A4 as a Target of the E3-Ligase Asb2β and Its Effect on Engineered Heart Tissue

et al. 2018

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“…26 However, its association with hypoxic CFs has yet to be investigated. Consistent with a previous study, 27 our results showed that β-catenin expression was elevated in CFs exposed to hypoxia ( Figure 6A-C), and this was accompanied by a greater ability to migrate and higher proliferation capacity ( Figure 4F-H). Furthermore, Xiang et al 28 demonstrated that the loss of β-catenin in mouse CFs attenuated cardiac fibrosis induced by pressure overload.…”

Section: Mir-145 and Sox9 Exert Their Effects By Regulating The Aktsupporting

confidence: 93%

miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

Cui¹,

Liu²,

Bo³

et al. 2020

J of Cellular Biochemistry

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Myocardial infarction (MI) will inevitably result in cardiac fibrosis. In this study, we investigated the effect of microRNA-145 (miR-145) and transcription factor sex-determining region Y box 9 (SOX9) in the production of cardiac fibrosis induced by MI. MI rat models were established by left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD, the cardiac fibrosis level was assessed by Masson's trichrome staining. Cardiac fibroblasts (CFs) exposed to hypoxia were used to simulate MI-induced fibrosis. Flow cytometry, cell counting kit-8, and transwell assays were used to examine changes in CF apoptosis, proliferation, and migration, respectively. miR-145 expression was measured by quantitative real-time polymerase chain reaction. Immunofluorescence and Western blot analysis were performed to determine the relative expression of proteins. In comparison to the sham-operated group, the expression of miR-145 was significantly downregulated in the infarction peripheral area, whereas, SOX9 was upregulated. In the infarcted heart, the overexpression of miR-145 significantly ameliorated cardiac fibrosis and cardiac function, and there was a negative correlation between miR-145 and SOX9 expressions in hypoxic CFs in vitro. In addition, SOX9 was verified to be a functional target of miR-145. Overexpression of miR-145 or inhibition of SOX9 decreased CF proliferation, migration, and fibrosis, but augmented their apoptotic rate. Moreover, the upregulation of miR-145 or suppression of SOX9 inhibited AKT and β-catenin signaling in hypoxic CFs. Taken together, this study highlights a potential treatment for cardiac fibrosis through the targeted regulation of SOX9 by miR-145, and our findings indicate that miR-145 exerts anti-fibrotic effects in MI via the negative regulation of SOX9 and its downstream AKT/GSK-3β/β-catenin pathways.

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“…Recent studies also directly demonstrated recombinant S100A4 protein elicited a robust hypertrophic response in cardiac myocytes, with an increased number of viable cells and inhibited apoptosis . Knockdown of S100A4 was reported to significantly suppress proliferation of cardiac fibroblasts and collagen expressions and thus could alleviate cardiac fibrosis . These findings suggested S100A4 may be potentially important for the pathogenesis of VMC.…”

Section: Discussionmentioning

confidence: 99%

“…28 Knockdown of S100A4 was reported to significantly suppress proliferation of cardiac fibroblasts and collagen expressions and thus could alleviate cardiac fibrosis. 13,29 These findings suggested S100A4 may be potentially important for the pathogenesis of VMC. In accordance with these studies, our present results, for the first time, showed that the expressions of S100A4 at mRNA and protein levels were significantly increased in VMC group compared with the control group.…”

Section: Discussionmentioning

confidence: 99%

Ginkgo biloba extract may alleviate viral myocarditis by suppression of S100A4 and MMP‐3

Wang

Liu

et al. 2019

Journal of Medical Virology

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Viral myocarditis (VMC) is an inflammatory cardiac disease caused by coxsackievirus B3 (CVB3) that leads to heart failure or sudden death. However, efficient therapeutic strategies for VMC remain lacking. Ginkgo biloba extract was previously demonstrated to have anti‐inflammatory activity and had been used in prevention and therapy of some cardiovascular diseases (ie myocardial infarction), indicating Ginkgo biloba extract may be a potential drug for the treatment of VMC. This study was, for the first time, to investigate the intervention effects of Ginkgo biloba extract on VMC model mice and explore its potential mechanisms. As a result, VMC mice model was successfully established by CVB3 infection, exhibiting significantly higher viral titer, serum creatine kinase isoenzyme level, heart weight/body weight ratio, histopathologic scores, collagen volume fraction (CVF), and significantly increased expression of S100A4 and matrix metalloproteinase‐3 (MMP‐3) at protein and messenger RNA levels compared with the control group. Also, the expression of S100A4 and MMP‐3/CVF was positively correlated. Ginkgo biloba extract treatment significantly reversed the trend in all the above parameters. Thus, Ginkgo biloba extract may be a promising therapeutic approach against VMC because it improved myocardial injury and alleviated the degree of myocardial fibrosis through suppression of S100A4 and MMP‐3.

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Downregulation of S100A4 Alleviates Cardiac Fibrosis via Wnt/β -Catenin Pathway in Mice

Cited by 36 publications

References 22 publications

S100A4 as a Target of the E3-Ligase Asb2β and Its Effect on Engineered Heart Tissue

S100A4 as a Target of the E3-Ligase Asb2β and Its Effect on Engineered Heart Tissue

miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

Ginkgo biloba extract may alleviate viral myocarditis by suppression of S100A4 and MMP‐3

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