WARP: A Unique Extracellular Matrix Component of Cartilage, Muscle, and Endothelial Cell Basement Membranes

Fitzgerald, Jamie

doi:10.1002/ar.24087

Cited by 17 publications

(20 citation statements)

References 27 publications

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“…Immunohistochemistry demonstrated SERPINH1/HSP47 to be highly expressed throughout the coronary vasculature and in fibroblasts in human heart, and weak staining was also detected in cardiomyocytes ( Figure 4E-G, Figure S7D). In human cardiac ECs, HSP47 was localized perinuclearly, similarly to what has been demonstrated in other cells types, and consistent with the ER retention motif in its N-terminus ( Figure 4E) [34][35][36] . We also tested, if exercise training can attenuate the expression of SerpinH1, Vwa1 and selected markers of TGF-b signaling/EndMT also in aged mice.…”

Section: Serpinh1 Expression Is Increased By Aging and Obesity And Resupporting

confidence: 86%

Cardiovascular disease risk factors induce mesenchymal features and senescence in cardiac endothelial cells

Hemanthakumar

Fang

Anisimov

et al. 2020

Preprint

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Aging, obesity, hypertension and physical inactivity are major risk factors for endothelial dysfunction and cardiovascular disease (CVD). We applied fluorescence-activated cell sorting (FACS), RNA sequencing and bioinformatic methods to investigate the common effects of CVD risk factors on cardiac endothelial cells (ECs). Aging, obesity and pressure overload all upregulated pathways related to TGF-b signaling and mesenchymal gene expression, inflammation, vascular permeability, oxidative stress, collagen synthesis and cellular senescence, whereas exercise training downregulated most of the same pathways. We identified collagen chaperone SerpinH1/HSP47 to be significantly increased by aging and obesity and repressed by exercise training. Mechanistic studies demonstrated that SERPINH1/HSP47 in human ECs changed cell morphology and increased mesenchymal gene expression, while its silencing inhibited collagen deposition. Our data demonstrate that CVD risk factors significantly remodel the transcriptomic landscape of cardiac ECs to acquire senescence and mesenchymal features. SERPINH1/HSP47 was identified as a potential therapeutic target in ECs.

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Section: Serpinh1 Expression Is Increased By Aging and Obesity And Resupporting

confidence: 86%

Cardiovascular disease risk factors induce mesenchymal features and senescence in cardiac endothelial cells

Hemanthakumar

Fang

Anisimov

et al. 2020

Preprint

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“…VWA1 was primarily known for its expression in cartilage cells, in basement membranes of the peripheral nervous system and in skeletal and cardiac muscle (Fitzgerald et al, 2002;Allen et al, 2008;Fitzgerald, 2019). Subsequent research also revealed a distinct localization of VWA1 in the inner ear vasculature, suggesting a potential role in maintaining its integrity (Duong et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent research also revealed a distinct localization of VWA1 in the inner ear vasculature, suggesting a potential role in maintaining its integrity ( Duong et al, 2011 ). Although VWA1 has surfaced in research on several diseases and has been suspected to be associated with neuro-musculoskeletal disorders, to date, no direct disease-causing variants have been directly identified ( Dieppedale et al, 2013 ; Fitzgerald, 2019 ). Zhang et al (2010) previously reported copy number variance of VWA1 and PYGO2 in a patient presenting with mandibulofacial dysostosis and microtia.…”

Section: Discussionmentioning

confidence: 99%

A Mutation in VWA1, Encoding von Willebrand Factor A Domain-Containing Protein 1, Is Associated With Hemifacial Microsomia

Wang

Luan

Chen

et al. 2020

Front. Cell Dev. Biol.

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Background: Hemifacial microsomia (HFM) is a type of rare congenital syndrome caused by developmental disorders of the first and second pharyngeal arches that occurs in one out of 5,600 live births. There are significant gaps in our knowledge of the pathogenic genes underlying this syndrome. Methods: Whole exome sequencing (WES) was performed on five patients, one asymptomatic carrier, and two marry-in members of a five-generation pedigree. Structure of WARP (product of VWA1) was predicted using the Phyre2 web portal. In situ hybridization and vwa1-knockdown/knockout studies in zebrafish using morpholino and CRISPR/Cas9 techniques were performed. Cartilage staining and immunofluorescence were carried out. Results: Through WES and a set of filtration, we identified a c.G905A:p.R302Q point mutation in a novel candidate pathogenic gene, VWA1. The Phyre2 web portal predicted alterations in secondary and tertiary structures of WARP, indicating changes in its function as well. Predictions of protein-to-protein interactions in five pathways related to craniofacial development revealed possible interactions with four proteins in the FGF pathway. Knockdown/knockout studies of the zebrafish revealed deformities of pharyngeal cartilage. A decrease of the proliferation of cranial neural crest cells (CNCCs) and alteration of the structure of pharyngeal chondrocytes were observed in the morphants as well.

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“…The PNPLA2 gene encodes a protein named adipose triglyceride lipase, which is expressed in human tumors and related to tumor aggressiveness 28 . The VWA1 gene encodes von Willebrand factor A-domain-related protein (WARP), the function of which is still unclear 29 . However, there is translational upregulation of VWA1 in hepatocellular carcinoma (HCC), and cell proliferation can be inhibited after knockdown of VWA1 30 .…”

Section: Discussionmentioning

confidence: 99%

Identification of aberrantly methylated-differentially expressed genes and potential agents for Ewing’s sarcoma

Gao

et al. 2020

Preprint

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Background DNA methylation is a common epigenetic regulatory way, and it plays a critical role in various human diseases. However, the potential role of how DNA methylation impacts Ewing’s sarcoma (ES) is not clear. This study aimed to explore the regulatory role of DNA methylation in ES. Methods The microarray data of gene expression and methylation were downloaded from Gene Expression Omnibus (GEO) database, and analyzed via GEO2R. Venn analysis was then applied to identify aberrantly methylated differentially expressed genes (DEGs). Subsequently, Function and pathway enrichment analysis was conducted. Protein-protein interaction (PPI) network was constructed. Hub genes were determined. Besides, a connectivity map (CMap) analysis was performed to screen bioactive compounds for ES treatment. Results A total of 135 hypomethylated high expression genes and 523 hypermethylated low expression genes were identified. The hypomethylated high expression genes were enriched in signal transduction and the apoptosis process. Meanwhile, hypermethylated low expression genes were related to DNA replication and transcription regulation. We next determined 10 hub genes through PPI analysis, among them, C3, TF, and TCEB1 might serve as diagnostic and therapeutic targets. Furthermore, CMap analysis revealed 6 chemicals as potential options for ES treatment. Conclusions For the first time, we jointly analyzed gene profiling and methylation data about ES. The introduction of DNA methylation characteristics over DEGs is helpful to understand the pathogenesis of ES. The identified hub aberrantly methylated DEGs and chemicals might provide some novel insights on ES treatment.

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WARP: A Unique Extracellular Matrix Component of Cartilage, Muscle, and Endothelial Cell Basement Membranes

Cited by 17 publications

References 27 publications

Cardiovascular disease risk factors induce mesenchymal features and senescence in cardiac endothelial cells

Cardiovascular disease risk factors induce mesenchymal features and senescence in cardiac endothelial cells

A Mutation in VWA1, Encoding von Willebrand Factor A Domain-Containing Protein 1, Is Associated With Hemifacial Microsomia

Identification of aberrantly methylated-differentially expressed genes and potential agents for Ewing’s sarcoma

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