Multiple Roles of sFRP2 in Cardiac Development and Cardiovascular Disease

Wu, Yu; Zheng, Haoxuan; Zhu, Hailan; Mai, Weiyi; Huang, Xiaohui; Huang, Yuli

doi:10.7150/ijbs.40923

Cited by 43 publications

(31 citation statements)

References 83 publications

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“…SFRPs may activate or inactivate Wnt-signaling and therefore, their role in the pathogenesis of AVS is currently unknown and remains controversial in other cardiac pathologies as well (Bovolenta et al, 2008;Foulquier et al, 2018). Of these molecules, SFRP2 is the most widely studied in the context of cardiac development and disease (Foulquier et al, 2018;Wu et al, 2020). For example, in animal models of myocardial infarction, SFRP2 gene deletion attenuated fibrosis and improved cardiac function, while treatment with SFRP2 antibody reduced apoptosis and fibrosis (Kobayashi et al, 2009;Mastri et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The Role of Wnt/β-Catenin Pathway Mediators in Aortic Valve Stenosis

Khan

Kiwan

et al. 2020

Front. Cell Dev. Biol.

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Aortic valve stenosis (AVS) is a prevailing and life-threatening cardiovascular disease in adults over 75 years of age. However, the molecular mechanisms governing the pathogenesis of AVS are yet to be fully unraveled. With accumulating evidence that Wnt signaling plays a key role in the development of AVS, the involvement of Wnt molecules has become an integral study target in AVS pathogenesis. Thus, we hypothesized that the Wnt/β-catenin pathway mediators, SFRP2, DVL2, GSK3β and β-catenin are dysregulated in patients with AVS. Using immunohistochemistry, Real-Time qPCR and Western blotting, we investigated the presence of SFRP2, GSK-3β, DVL2, and β-catenin in normal and stenotic human aortic valves. Markedly higher mRNA and protein expression of GSK-3β, DVL2, β-catenin and SFRP2 were found in stenotic aortic valves. This was further corroborated by observation of their abundant immunostaining, which displayed strong immunoreactivity in diseased aortic valves. Proteomic analyses of selective GSK3b inhibition in calcifying human aortic valve interstitial cells (HAVICs) revealed enrichment of proteins involved organophosphate metabolism, while reducing the activation of pathogenic biomolecular processes. Lastly, use of the potent calcification inhibitor, Fetuin A, in calcifying HAVICs significantly reduced the expression of Wnt signaling genes Wnt3a, Wnt5a, Wnt5b, and Wnt11. The current findings of altered expression of canonical Wnt signaling in AVS suggest a possible role for regulatory Wnts in AVS. Hence, future studies focused on targeting these molecules are warranted to underline their role in the pathogenesis of the disease.

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Section: Discussionmentioning

confidence: 99%

The Role of Wnt/β-Catenin Pathway Mediators in Aortic Valve Stenosis

Khan

Kiwan

et al. 2020

Front. Cell Dev. Biol.

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“…30 As a vital molecule of the Wnt signaling, sFRP2 can regulate cardiac development and cardiovascular disease. 31 MiRNAs as a class of small noncoding RNAs play a central role in cardiogenesis, heart function, and pathology. 32,33 It has been reported that miR-142 contributes to early cardiomyocyte differentiation of mouse ES cells, 34 miR-335 could regulate human cardiac mesoderm and progenitor cell differentiation, 35 whereas miR-130 acts as a necessary linkage for the negative Fgf8-Bmp2 feed-back as responsible to achieve early cardiac specification.…”

Section: Discussionmentioning

confidence: 99%

MiR-184 directly targets Wnt3 in cardiac mesoderm differentiation of embryonic stem cells

et al. 2020

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Embryonic stem (ES) cells have the property of self-renewal and multi-directional differentiation, and provide an ideal model for studying early embryo development in vitro. Wnt3, as Wnt family member 3, plays a vital role during ES cell differentiation. However, the exact regulatory mechanism of Wnt3 remains to be elucidated. MicroRNAs can directly regulate gene expression at the post-transcriptional level and play critical function in cell fate determination. Here, we found the expression level of miR-184 decreased when ES cells differentiated into cardiac mesoderm then increased during the process as differentiated into cardiomyocytes, which negatively correlated with the expression of Wnt3. Overexpression of miR-184 during the process of ES cell differentiation into cardiac mesoderm repressed cardiac mesoderm differentiation and cardiomyocyte formation. Bioinformatics prediction and mechanism studies showed that miR-184 directly bound to the 3′UTR region of Wnt3 and inhibited the expression level of Wnt3. Consistently, knockdown of Wnt3 mimicked the effects of miR-184-overexpression on ES cell differentiation into cardiac mesoderm, whereas overexpression of Wnt3 rescued the inhibition effects of miR-184 overexpression on ES cell differentiation. These findings demonstrated that miR-184 is a direct regulator of Wnt3 during the differentiation process of ES cells, further enriched the epigenetic regulatory network of ES cell differentiation into cardiac mesoderm and cardiomyocytes.

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“…The GO and pathway enrichment analysis of DEG are closely related to obesity associated type 2 diabetes mellitus genes and advancement. KCNE5 [45], SHANK3 [46], CASQ2 [47], EDNRA (endothelin receptor type A) [48], EPHB4 [49], ALPK3 [50], WNT11 [51], IRAK2 [52], FBN1 [53], SFRP2 [54], CLCA2 [55], NEXN (nexilin F-actin binding protein) [56], PALLD (palladin, cytoskeletal associated protein) [57], DAB2 [58], NRP2 [59], THBS2 [60], CSF1R [61], KCNA2 [62], CACNA1C [63], F2R [64], UCHL1 [65], CCL18 [66], ITGB1BP2 [67] and FMOD ( bromodulin) [68] were reportedly involved in cardio vascular diseases, but these genes might be key for progression of obesity associated type 2 diabetes mellitus. Hu et al [69], Liu et al [70], Eltokhi et al [71], Cai et al [72], Pfeiffer et al [73], Lin et al [74], Royer-Zemmour et al [75], Pastor et al [76], Goodspeed et al [77], Zhang et al [78], Rogers et al [79], Su et al [80] and Foale et al [81] reported that NRXN1, CRHR1, SHANK2, PSEN2, CKB (creatine kinase B), CD200R1, SRPX2, PTPRZ1, SLC6A1, GABRB2, KCNA1, ASAH1 and LINGO1 were linked with progression of neuropsychiatric disorders, but these genes might be involved in advancement of obesity associated type 2 diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules 

Prashanth

Vastrad²,

Tengli

et al. 2020

Preprint

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BackgroundObesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the development mechanism of obesity associated type 2 diabetes mellitus. MethodsTo screen the differentially expressed genes (DEGs) that may play essential roles in obesity associated type 2 diabetes mellitus, the public expression profiling by high throughput sequencing data (GSE143319) were downloaded and screened for DEGs. Then, Gene Ontology (GO) function analysis and REACTOME pathway analysis were performed. To screen hub and target genes, the protein–protein interaction network, miRNA-target genes regulatory network and TF-target gene regulatory network were constructed. The Receiver operating characteristic (ROC) curve analysis and RT- PCR analysis of hub genes in obesity associated type 2 diabetes mellitus were also analyzed. Final molecular docking studies performed for screening small drug molecules. ResultsThere were 409 up regulated and 411 down regulated genes detected, and the biological processes of the GO analysis were enriched in regulation of ion transmembrane transport, intrinsic component of plasma membrane, transferase activity, transferring phosphorus-containing groups, cell adhesion, integral component of plasma membrane and signaling receptor binding, whereas, the REACTOME pathway analysis was enriched in integration of energy metabolism and extracellular matrix organization. The hub genes CEBPD, TP73, ESR2, TAB1, MAP3K5, FN1, UBD, RUNX1, PIK3R2 and TNF, which might play a essential role in obesity associated type 2 diabetes mellitus was further screened. ConclusionsThe present study could deepen the understanding of the molecular mechanism of obesity associated type 2 diabetes mellitus, which could be useful in developing clinical treatments of obesity associated type 2 diabetes mellitus.

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Multiple Roles of sFRP2 in Cardiac Development and Cardiovascular Disease

Cited by 43 publications

References 83 publications

The Role of Wnt/β-Catenin Pathway Mediators in Aortic Valve Stenosis

The Role of Wnt/β-Catenin Pathway Mediators in Aortic Valve Stenosis

MiR-184 directly targets Wnt3 in cardiac mesoderm differentiation of embryonic stem cells

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules

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Multiple Roles of sFRP2 in Cardiac Development and Cardiovascular Disease

Cited by 43 publications

References 83 publications

The Role of Wnt/β-Catenin Pathway Mediators in Aortic Valve Stenosis

The Role of Wnt/β-Catenin Pathway Mediators in Aortic Valve Stenosis

MiR-184 directly targets Wnt3 in cardiac mesoderm differentiation of embryonic stem cells

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules&nbsp;

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Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules