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Goniothalamin induces coronary artery smooth muscle cells apoptosis: the p53-dependent caspase-2 activation pathway.
- 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 Year :
- 2010
-
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.
- Subjects :
- 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
Apoptosis drug effects
Caspase 2 metabolism
Muscle, Smooth, Vascular drug effects
Myocytes, Smooth Muscle drug effects
Pyrones toxicity
Tumor Suppressor Protein p53 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0929
- Volume :
- 116
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxicological sciences : an official journal of the Society of Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 20498002
- Full Text :
- https://doi.org/10.1093/toxsci/kfq151