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Proteomic-based detection of a protein cluster dysregulated during cardiovascular development identifies biomarkers of congenital heart defects
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America; Department of Pathology, Yale University, New Haven, Connecticut, United States of America.
Department of Pathology, Yale University, New Haven, Connecticut, United States of America.
Department of Pathology, Yale University, New Haven, Connecticut, United States of America.
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America.
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2009 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 1, article id e4221Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Cardiovascular development is vital for embryonic survival and growth. Early gestation embryo loss or malformation has been linked to yolk sac vasculopathy and congenital heart defects (CHDs). However, the molecular pathways that underlie these structural defects in humans remain largely unknown hindering the development of molecular-based diagnostic tools and novel therapies.

METHODOLOGY/PRINCIPAL FINDINGS: Murine embryos were exposed to high glucose, a condition known to induce cardiovascular defects in both animal models and humans. We further employed a mass spectrometry-based proteomics approach to identify proteins differentially expressed in embryos with defects from those with normal cardiovascular development. The proteins detected by mass spectrometry (WNT16, ST14, Pcsk1, Jumonji, Morca2a, TRPC5, and others) were validated by Western blotting and immunoflorescent staining of the yolk sac and heart. The proteins within the proteomic dataset clustered to adhesion/migration, differentiation, transport, and insulin signaling pathways. A functional role for several proteins (WNT16, ADAM15 and NOGO-A/B) was demonstrated in an ex vivo model of heart development. Additionally, a successful application of a cluster of protein biomarkers (WNT16, ST14 and Pcsk1) as a prenatal screen for CHDs was confirmed in a study of human amniotic fluid (AF) samples from women carrying normal fetuses and those with CHDs.

CONCLUSIONS/SIGNIFICANCE: The novel finding that WNT16, ST14 and Pcsk1 protein levels increase in fetuses with CHDs suggests that these proteins may play a role in the etiology of human CHDs. The information gained through this bed-side to bench translational approach contributes to a more complete understanding of the protein pathways dysregulated during cardiovascular development and provides novel avenues for diagnostic and therapeutic interventions, beneficial to fetuses at risk for CHDs.

Place, publisher, year, edition, pages
PLOS , 2009. Vol. 4, no 1, article id e4221
National Category
Cardiac and Cardiovascular Systems
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URN: urn:nbn:se:oru:diva-70927DOI: 10.1371/journal.pone.0004221ISI: 000265481900004PubMedID: 19156209Scopus ID: 2-s2.0-64149126449OAI: oai:DiVA.org:oru-70927DiVA, id: diva2:1345913
Available from: 2019-08-26 Created: 2019-08-26 Last updated: 2019-08-28Bibliographically approved

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