Monocrotaline pyrrole induces Smad nuclear accumulation and altered signaling expression in human pulmonary arterial endothelial cells.

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  • Author(s): Ramos M;Ramos M; Lamé MW; Segall HJ; Wilson DW
  • Source:
    Vascular pharmacology [Vascul Pharmacol] 2007 Jun; Vol. 46 (6), pp. 439-48. Date of Electronic Publication: 2007 Feb 02.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: United States NLM ID: 101130615 Publication Model: Print-Electronic Cited Medium: Print ISSN: 1537-1891 (Print) Linking ISSN: 15371891 NLM ISO Abbreviation: Vascul Pharmacol Subsets: MEDLINE
    • Publication Information:
      Original Publication: New York, NY : Elsevier Science, c2002-
    • Subject Terms:
      Alkylating Agents/*toxicity ; Cell Nucleus/*drug effects ; Endothelial Cells/*drug effects ; Monocrotaline/*analogs & derivatives ; Pulmonary Artery/*drug effects ; Signal Transduction/*drug effects ; Smad Proteins/*metabolism; Active Transport, Cell Nucleus/drug effects ; Bone Morphogenetic Protein Receptors, Type II/metabolism ; Bone Morphogenetic Proteins/metabolism ; Bone Morphogenetic Proteins/pharmacology ; Caveolae/drug effects ; Caveolae/ultrastructure ; Cell Nucleus/metabolism ; Cells, Cultured ; Child, Preschool ; Endothelial Cells/metabolism ; Endothelial Cells/ultrastructure ; Female ; Humans ; Monocrotaline/toxicity ; Phosphorylation ; Pulmonary Artery/metabolism ; Pulmonary Artery/pathology ; Smad Proteins/genetics ; Smad1 Protein/metabolism ; Smad2 Protein/metabolism ; Smad4 Protein/metabolism ; Smad6 Protein/metabolism ; Time Factors ; Transfection ; Transforming Growth Factor beta1/metabolism ; Transforming Growth Factor beta1/pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism
    • Abstract:
      The mechanistic relationship between the widely used monocrotaline model of primary pulmonary hypertension and altered TGFbeta family signaling due to genetic defects in the Bone Morphogenetic Protein type II receptor in affected humans has not been investigated. In this study we use fluorescent microscopy to demonstrate nuclear translocation of Smad 4 in human pulmonary arterial endothelial cell (HPAEC) cultures treated with monocrotaline pyrrole (MCTP), Bone Morphogenetic Protein (BMP) and TGFbeta. While MCTP induced transient nuclear accumulation of phosphorylated Smad 1 (P-Smad 1) and phosphorylated Smad 2 (P-Smad 2), only expression of P-Smad 1 was significantly altered in western blots. P-Smad 1 expression significantly increased 30 min following treatment with MCTP correlating with P-Smad 1 and Smad 4 nuclear translocation. Although a modest, but significant decrease in P-Smad 1 expression occurred 1 h after treatment, expression was significantly increased at 72 h. Evaluation of components of the signal and response pathway at 72 h showed decreased expression of the BMP type II receptor (BMPrII), no change in TGFbeta Activin Receptor-like Kinase 1 (Alk 1), no change in Smad 4 but increase in the inhibitory Smad 6, decrease in the alternate BMP signaling pathway p38(MAPK) but no change in the psmad1 response element ID 1. Our results suggest transient activation of Smad signaling pathways in initial MCTP endothelial cell toxicity, and a persistent dysregulation of BMP signaling. Electron microscopy of cell membrane caveoli revealed a dramatic decrease in these structures after 72 h. Loss of these structural elements, noted for their sequestration and inhibition of receptor activity, may contribute to prolonged alterations in BMP signaling.
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    • Grant Information:
      R01 HL048411-13 United States HL NHLBI NIH HHS; T32 ES007055-28 United States ES NIEHS NIH HHS; ES070555 United States ES NIEHS NIH HHS; HL48411 United States HL NHLBI NIH HHS; T32 ES007055-26 United States ES NIEHS NIH HHS; R01 HL048411-12 United States HL NHLBI NIH HHS; T32 ES007055-27 United States ES NIEHS NIH HHS; R01 HL048411 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Alkylating Agents)
      0 (Bone Morphogenetic Proteins)
      0 (SMAD1 protein, human)
      0 (SMAD2 protein, human)
      0 (SMAD4 protein, human)
      0 (SMAD6 protein, human)
      0 (Smad Proteins)
      0 (Smad1 Protein)
      0 (Smad2 Protein)
      0 (Smad4 Protein)
      0 (Smad6 Protein)
      0 (Transforming Growth Factor beta1)
      23291-96-5 (monocrotaline pyrrole)
      73077K8HYV (Monocrotaline)
      EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
      EC 2.7.11.30 (Bone Morphogenetic Protein Receptors, Type II)
    • Publication Date:
      Date Created: 20070306 Date Completed: 20070614 Latest Revision: 20241119
    • Publication Date:
      20241119
    • Accession Number:
      PMC2570208
    • Accession Number:
      10.1016/j.vph.2007.01.005
    • Accession Number:
      17336165