Goniothalamin induces coronary artery smooth muscle cells apoptosis: the p53-dependent caspase-2 activation pathway.

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  • Author(s): Chan KM;Chan KM; Rajab NF; Siegel D; Din LB; Ross D; Inayat-Hussain SH
  • Source:
    Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2010 Aug; Vol. 116 (2), pp. 533-48. Date of Electronic Publication: 2010 May 24.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Oxford University Press Country of Publication: United States NLM ID: 9805461 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0929 (Electronic) Linking ISSN: 10960929 NLM ISO Abbreviation: Toxicol Sci Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Cary, NC : Oxford University Press
      Original Publication: Orlando, FL : Academic Press, c1998-
    • Subject Terms:
      Apoptosis/*drug effects ; Caspase 2/*metabolism ; Muscle, Smooth, Vascular/*drug effects ; Myocytes, Smooth Muscle/*drug effects ; Pyrones/*toxicity ; Tumor Suppressor Protein p53/*physiology; Adenosine Triphosphate/analysis ; Amino Acid Chloromethyl Ketones/pharmacology ; Cells, Cultured ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation ; Humans ; Hydrogen Peroxide/metabolism ; Membrane Potential, Mitochondrial/drug effects ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; Oxygen Consumption/drug effects ; Superoxides/metabolism
    • Abstract:
      Goniothalamin (GN), a styryl-lactone isolated from Goniothalamus andersonii, has been demonstrated to possess antirestenostic properties by inducing apoptosis on coronary artery smooth muscle cells (CASMCs). In this study, the molecular mechanisms of GN-induced CASMCs apoptosis were further elucidated. Apoptosis assessment based on the externalization of phosphatidylserine demonstrated that GN induces CASMCs apoptosis in a concentration-dependent manner. The GN-induced DNA damage occurred with concomitant elevation of p53 as early as 2 h, demonstrating an upstream signal for apoptosis. However, the p53 elevation in GN-treated CASMCs was independent of NAD(P)H: quinone oxidoreductase 1 and Mdm-2 expression. An increase in hydrogen peroxide and reduction in free thiols confirmed the role for oxidative stress in GN treatment. Pretreatment with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-FMK) that significantly abrogated GN-induced CASMCs apoptosis suggested the involvement of caspase(s). The role of apical caspase-2, -8, and -9 was then investigated, and sequential activation of caspase-2 and -9 but not caspase-8 leading to downstream caspase-3 cleavage was observed in GN-treated CASMCs. Reduction of ATP level and decrease in oxygen consumption further confirmed the role of mitochondria in GN-induced apoptosis in CASMCs. The mitochondrial release of cytochrome c was seen without mitochondrial membrane potential loss and was independent of cardiolipin. These data provide insight into the mechanisms of GN-induced apoptosis, which may have important implications in the development of drug-eluting stents.
    • Accession Number:
      0 (Amino Acid Chloromethyl Ketones)
      0 (Pyrones)
      0 (Tumor Suppressor Protein p53)
      0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
      11062-77-4 (Superoxides)
      34W9GO6B2Z (goniothalamin)
      8L70Q75FXE (Adenosine Triphosphate)
      9007-43-6 (Cytochromes c)
      BBX060AN9V (Hydrogen Peroxide)
      EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone))
      EC 1.6.5.2 (NQO1 protein, human)
      EC 3.4.22.- (Caspase 2)
    • Publication Date:
      Date Created: 20100526 Date Completed: 20101028 Latest Revision: 20181201
    • Publication Date:
      20250114
    • Accession Number:
      10.1093/toxsci/kfq151
    • Accession Number:
      20498002