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      O-linked β-N-acetylglucosamine transferase plays an essential role in heart development through regulating angiopoietin-1

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          Abstract

          O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) is the only enzyme catalyzing O-GlcNAcylation. Although it has been shown that OGT plays an essential role in maintaining postnatal heart function, its role in heart development remains unknown. Here we showed that loss of OGT in early fetal cardiomyocytes led to multiple heart developmental defects including hypertrabeculation, biventricular dilation, atrial septal defects, ventricular septal defects, and defects in coronary vessel development. In addition, RNA sequencing revealed that Angiopoietin-1, required within cardiomyocytes for both myocardial and coronary vessel development, was dramatically downregulated in cardiomyocyte-specific OGT knockout mouse hearts. In conclusion, our data demonstrated that OGT plays an essential role in regulating heart development through activating expression of cardiomyocyte Angiopoietin-1.

          Author summary

          As the first functional organ to form, the heart develops from a simple tube to a complex organ with four chambers to keep up with the body’s increasing demand for blood. During this period, myocardium, the major component of heart, undergoes substantial dynamic architectural remodeling at different levels. This remodeling also coincides with coronary vessel development to form a functional heart. Defects in architectural remodeling of myocardium or coronary vessel development can lead to anatomical changes during heart development, resulting in congenital heart disease. O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) is the only enzyme catalyzing protein O-GlcNAcylation using UDP-GlcNAc, the end product of the hexosamine biosynthetic pathway. Hence, OGT is also considered a sensor of cellular nutrient levels. In this study, we found that loss of OGT in myocardium disrupted myocardial remodeling, as well as coronary vessel development, through regulating Angiopoietin-1 expression. Our study not only demonstrates an essential role for myocardial OGT during heart development, but also has potential implications for the development of new treatment options targeting coronary diseases.

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          Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc.

          C. R. TORRES, G W Hart (1984)
          Bovine milk galactosyltransferase has been used, in conjunction with UDP-[3H]galactose, as an impermeant probe for accessible GlcNAc residues on the surfaces of lymphocytes. Galactosylation of living thymic lymphocytes is dependent upon cell number, enzyme concentration, UDP-galactose concentration, and Mn2+ concentration. Kinetics of labeling are biphasic, leveling off at approximately 30 min. The data strongly indicate vectorial surface labeling and covalent attachment of galactose. Thymocytes, T-lymphocytes, and B-lymphocytes have approximately 10(6), 3 X 10(6), and 5 X 10(6) galactosylatable sites on their cell surfaces, respectively. Numerous proteins are exogalactosylated that differ quantitatively among the major functional subsets of lymphocytes. Negligible radioactivity is found in lipid. In thymocytes, 49% of the exogalactosylated oligosaccharides are alkali labile, whereas 80 and 90% of that derived from T-lymphocytes and B-lymphocytes can be beta-eliminated, respectively. Sensitivity of the intact proteins or tryptic peptides to the peptide: N-glycosidase also confirms the relative amounts of cell surface, N-linked and O-linked oligosaccharides which are exogalactosylated. Composition, size, and high performance liquid chromatography on two types of high resolution columns establish that the bulk of the exogalactosylated, beta-eliminated oligosaccharides are Gal beta 1-4GlcNAcitol. These data suggest the presence of O-glycosidically linked GlcNAc monosaccharide on many lymphocyte cell-surface proteins. However, additional experiments indicate that the majority of these moieties appear to be cryptic or inside the cell. Thus, these studies not only describe dramatic differences in the amounts and distribution of terminal GlcNAc residues on phenotypically different lymphocyte populations, but they also describe the presence of a novel protein-saccharide linkage, which is present on numerous lymphocyte proteins.
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            A little sugar goes a long way: The cell biology of O-GlcNAc

            Michelle Bond, John Hanover (2015)
            Unlike the complex glycans decorating the cell surface, the O-linked β-N-acetyl glucosamine (O-GlcNAc) modification is a simple intracellular Ser/Thr-linked monosaccharide that is important for disease-relevant signaling and enzyme regulation. O-GlcNAcylation requires uridine diphosphate–GlcNAc, a precursor responsive to nutrient status and other environmental cues. Alternative splicing of the genes encoding the O-GlcNAc cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) yields isoforms targeted to discrete sites in the nucleus, cytoplasm, and mitochondria. OGT and OGA also partner with cellular effectors and act in tandem with other posttranslational modifications. The enzymes of O-GlcNAc cycling act preferentially on intrinsically disordered domains of target proteins impacting transcription, metabolism, apoptosis, organelle biogenesis, and transport.
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              Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies

              Agnieszka Zimna, Maciej Kurpisz (2015)
              The cardiovascular system ensures the delivery of oxygen and nutrients to all cells, tissues, and organs. Under extended exposure to reduced oxygen levels, cells are able to survive through the transcriptional activation of a series of genes that participate in angiogenesis, glucose metabolism, and cell proliferation. The oxygen-sensitive transcriptional activator HIF-1 (hypoxia-inducible factor-1) is a key transcriptional mediator of the response to hypoxic conditions. The HIF-1 pathway was found to be a master regulator of angiogenesis. Whether the process is physiological or pathological, HIF-1 seems to participate in vasculature formation by synergistic correlations with other proangiogenic factors such as VEGF (vascular endothelial growth factor), PlGF (placental growth factor), or angiopoietins. Considering the important contributions of HIF-1 in angiogenesis and vasculogenesis, it should be considered a promising target for treating ischaemic diseases or cancer. In this review, we discuss the roles of HIF-1 in both physiological/pathophysiological angiogenesis and potential strategies for clinical therapy.
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                Author and article information

                Contributors
                Yongxin Mu: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draft
                Houzhi Yu:
                ORCID: http://orcid.org/0000-0003-2973-6081
                Role: InvestigationRole: MethodologyRole: Validation
                Tongbin Wu:
                ORCID: http://orcid.org/0000-0001-6232-3268
                Role: Methodology
                Jianlin Zhang: Role: Methodology
                Sylvia M. Evans: Role: Formal analysisRole: Writing – review & editing
                Ju Chen:
                ORCID: http://orcid.org/0000-0001-7674-4776
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Anthony B. Firulli: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS Genet
                Journal ID (iso-abbrev): PLoS Genet
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosgen
                Title: PLoS Genetics
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Print): 1553-7390
                ISSN (Electronic): 1553-7404
                Publication date (Electronic): 6 April 2020
                Publication date Collection: April 2020
                Volume: 16
                Issue: 4
                Electronic Location Identifier: e1008730
                Affiliations
                [1 ] Department of Medicine-Cardiology, University of California San Diego,Gilman Drive, Mail Code, La Jolla, California, United States of America
                [2 ] Department of Cardiology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
                [3 ] Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA, United States of America
                Indiana University Purdue University at Indianapolis, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-2973-6081
                http://orcid.org/0000-0001-6232-3268
                http://orcid.org/0000-0001-7674-4776
                Article
                Publisher ID: PGENETICS-D-20-00081
                DOI: 10.1371/journal.pgen.1008730
                PMC ID: 7182263
                PubMed ID: 32251422
                SO-VID: e6adb953-14d9-44d6-86d0-727e715668c8
                Copyright © © 2020 Mu et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 17 January 2020
                Date accepted : 20 March 2020
                Page count
                Figures: 6, Tables: 0, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: 1R01HL146759
                Award Recipient :
                ORCID: http://orcid.org/0000-0001-7674-4776
                JC is supported by grants R01HL146759, R01HL144872, and R01HL137957 from the National Institutes of Health. SME is supported by grant R35HL144984 from the National Institutes of Health. JC is the American Heart Association (AHA) Endowed Chair in Cardiovascular Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Cardiovascular Anatomy
                Subject: Heart
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Cardiovascular Anatomy
                Subject: Heart
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Muscle Cells
                Subject: Cardiomyocytes
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Muscle Tissue
                Subject: Muscle Cells
                Subject: Cardiomyocytes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Muscle Tissue
                Subject: Muscle Cells
                Subject: Cardiomyocytes
                Subject: Research and Analysis Methods
                Subject: Animal Studies
                Subject: Experimental Organism Systems
                Subject: Model Organisms
                Subject: Mouse Models
                Subject: Research and Analysis Methods
                Subject: Model Organisms
                Subject: Mouse Models
                Subject: Research and Analysis Methods
                Subject: Animal Studies
                Subject: Experimental Organism Systems
                Subject: Animal Models
                Subject: Mouse Models
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Embryology
                Subject: Embryos
                Subject: Research and Analysis Methods
                Subject: Specimen Preparation and Treatment
                Subject: Staining
                Subject: Immunostaining
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Organism Development
                Subject: Organogenesis
                Subject: Heart Development
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Cardiovascular Anatomy
                Subject: Blood Vessels
                Subject: Arteries
                Subject: Coronary Arteries
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Cardiovascular Anatomy
                Subject: Blood Vessels
                Subject: Arteries
                Subject: Coronary Arteries
                Subject: Medicine and Health Sciences
                Subject: Congenital Disorders
                Subject: Birth Defects
                Subject: Congenital Heart Defects
                Subject: Ventricular Septal Defects
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Morphogenesis
                Subject: Birth Defects
                Subject: Congenital Heart Defects
                Subject: Ventricular Septal Defects
                Subject: Medicine and Health Sciences
                Subject: Cardiology
                Subject: Congenital Heart Defects
                Subject: Ventricular Septal Defects
                Custom metadata
                PLOS Publication Stage vor-update-to-uncorrected-proof
                Publication Update 2020-04-24
                Data Availability All relevant data are within the manuscript and its Supporting Information files except for the RNAseq data, which can be accessed from the GEO database using accession number GSE146962.

                ScienceOpen disciplines: Genetics
                Data availability:
                ScienceOpen disciplines: Genetics

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