Audi Setiadi

BC Cancer Agency, Vancouver, British Columbia, Canada

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Publications (3)14.97 Total impact

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    ABSTRACT: The heart is the first organ to form during embryogenesis, and cardiac malformations are the most frequent congenital birth defects, present in ~1-2% of newborns. Valvuloseptal defects, including atrioventricular canal (AVC) defects, pulmonary atresia/stenosis, and a combination of these referred to as Tetralogy of Fallot are the most common. A key process in valve and septum development is the formation, differentiation and remodeling of cardiac cushion that eventually partitions the atria and ventricles, and ventricular outflow tract, into the dorsal aorta and pulmonary artery. Cardiac cushion development is initiated when cardiac endothelial cells (EC) undergo mesenchymal transformation (EndMT) and invade the underlying extracellular matrix (cardiac jelly). Both endocardium and myocardium play a role in EndMT. Notch activation in EC induces EndMT. At E9.5, Notch signaling induces EndMT in the AVC, where the cardiac cushions eventually develop into heart valves and the cardiac septum. Mutation and disruptions of the Notch pathway result in cardiac malformations. We have shown that Notch activates nitric oxide (NO) signaling to initiate EndMT in the developing AVC. We used global gene expression analysis to identify the soluble guanylyl cyclase (sGC) 1A3 and 1B3 genes, which form the NO receptor heterodimer, as novel Notch targets. We also showed that Notch signaling induces EC-NO production in a paracrine fashion. Ex vivo AVC explant assays showed that NO-sGC activation contributes to cell migration and invasion at the start of EndMT. Thus we conclude that during AVC EndMT, Notch signaling activates the NO pathway by upregulating the sGC in transforming EC, and secreting a paracrine factor to induce NO synthesis. These findings offer new insight into Notch-driven EndMT in AVC development and may be transferrable to other EndMT pathologies such as cancer. This work was supported by Genome BC, Genome Canada, Heart & Stroke Foundation, and CIHR grant MOP-64354.
    American Association for the Advancement of Science 2012 Annual Meeting; 02/2012
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    ABSTRACT: The heart is the most common site of congenital defects, and valvuloseptal defects are the most common of the cardiac anomalies seen in the newborn. The process of endothelial-to-mesenchymal transition (EndMT) in the cardiac cushions is a required step during early valve development, and Notch signaling is required for this process. Here we show that Notch activation induces the transcription of both subunits of the soluble guanylyl cyclase (sGC) heterodimer, GUCY1A3 and GUCY1B3, which form the nitric oxide receptor. In parallel, Notch also promotes nitric oxide (NO) production by inducing Activin A, thereby activating a PI3-kinase/Akt pathway to phosphorylate eNOS. We thus show that the activation of sGC by NO through a Notch-dependent autocrine loop is necessary to drive early EndMT in the developing atrioventricular canal (AVC).
    Developmental Cell 08/2011; 21(2):288-300. · 10.37 Impact Factor
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    ABSTRACT: Notch and transforming growth factor beta (TGFbeta) play critical roles in endothelial-to-mesenchymal transition (EndMT), a process that is essential for heart development. Previously, we have shown that Notch and TGFbeta signaling synergistically induce Snail expression in endothelial cells, which is required for EndMT in cardiac cushion morphogenesis. Here, we report that Notch activation modulates TGFbeta signaling pathways in a receptor-activated Smad (R-Smad)-specific manner. Notch activation inhibits TGFbeta/Smad1 and TGFbeta/Smad2 signaling pathways by decreasing the expression of Smad1 and Smad2 and their target genes. In contrast, Notch increases SMAD3 mRNA expression and protein half-life and regulates the expression of TGFbeta/Smad3 target genes in a gene-specific manner. Inhibition of Notch in the cardiac cushion of mouse embryonic hearts reduces Smad3 expression. Notch and TGFbeta synergistically up-regulate a subset of genes by recruiting Smad3 to both Smad and CSL binding sites and cooperatively inducing histone H4 acetylation. This is the first evidence that Notch activation affects R-Smad expression and that cooperative induction of histone acetylation at specific promoters underlies the selective synergy between Notch and TGFbeta signaling pathways.
    Journal of Biological Chemistry 06/2009; 284(29):19452-62. · 4.60 Impact Factor

Publication Stats

62 Citations
14.97 Total Impact Points

Institutions

  • 2012
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
  • 2011
    • Michael Smith Genome Sciences Centre
      Calgary, Alberta, Canada
  • 2009
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada