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Fetal Mouse Cardiovascular Imaging Using a High-frequency Ultrasound (30/45MHZ) System
Published on: May 5, 2018
Proteomic-based detection of a protein cluster dysregulated during cardiovascular development identifies biomarkers
Anjali K Nath1, Michael Krauthammer, Puyao Li
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America. anjali.nath@aya.yale.edu
Insights
Congenital heart defects (CHDs) in fetuses are linked to altered WNT16, ST14, and Pcsk1 protein levels. These findings offer new diagnostic and therapeutic strategies for prenatal screening and understanding cardiovascular development.
Area of Science:
- Developmental Biology
- Cardiovascular Science
- Proteomics
Background:
- Cardiovascular development is crucial for embryonic survival, with defects linked to yolk sac vasculopathy and congenital heart defects (CHDs).
- Molecular pathways underlying human CHDs are largely unknown, limiting diagnostic and therapeutic advancements.
Purpose of the Study:
- To identify molecular pathways and protein biomarkers associated with cardiovascular defects during embryonic development.
- To explore the potential of identified proteins as prenatal diagnostic markers for CHDs.
Main Methods:
- Murine embryos were exposed to high glucose to induce cardiovascular defects.
- Mass spectrometry-based proteomics identified differentially expressed proteins.
- Protein validation using Western blotting and immunofluorescence.
- Functional analysis of proteins in an ex vivo heart development model.
- Prenatal screening for CHDs using amniotic fluid samples.
Main Results:
- Proteomic analysis identified key proteins including WNT16, ST14, and Pcsk1.
- Identified proteins are involved in adhesion/migration, differentiation, transport, and insulin signaling pathways.
- WNT16, ADAM15, and NOGO-A/B demonstrated functional roles in heart development.
- A panel of WNT16, ST14, and Pcsk1 proteins showed success as a prenatal screen for CHDs in human amniotic fluid.
Conclusions:
- Elevated WNT16, ST14, and Pcsk1 protein levels in fetuses with CHDs suggest their involvement in CHD etiology.
- This translational research enhances understanding of dysregulated protein pathways in cardiovascular development.
- Provides novel avenues for diagnostic and therapeutic interventions for fetuses at risk of CHDs.
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.
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