Goniothalamin induces coronary artery smooth muscle cells apoptosis

The p53-dependent caspase-2 activation pathway

Chan Kok Meng, Nor Fadilah Rajab, David Siegel, Laily Bin Din, David Ross, Salmaan Hussain Inayat-Hussain

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 pancaspase 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.

Original languageEnglish
Pages (from-to)533-548
Number of pages16
JournalToxicological Sciences
Volume116
Issue number2
DOIs
Publication statusPublished - 4 Feb 2010

Fingerprint

Caspase 2
Smooth Muscle Myocytes
Muscle
Coronary Vessels
Chemical activation
Cells
Apoptosis
Caspase 8
Goniothalamus
goniothalamin
Mitochondria
Cardiolipins
Drug-Eluting Stents
Stents
Oxidative stress
Caspase 9
Mitochondrial Membrane Potential
Phosphatidylserines
Lactones
Caspases

Keywords

  • Caspases
  • Coronary artery smooth muscle cells
  • Goniothalamin
  • Mitochondrial-mediated apoptosis
  • NQO1
  • P53

ASJC Scopus subject areas

  • Toxicology

Cite this

Goniothalamin induces coronary artery smooth muscle cells apoptosis : The p53-dependent caspase-2 activation pathway. / Kok Meng, Chan; Rajab, Nor Fadilah; Siegel, David; Din, Laily Bin; Ross, David; Inayat-Hussain, Salmaan Hussain.

In: Toxicological Sciences, Vol. 116, No. 2, 04.02.2010, p. 533-548.

Research output: Contribution to journalArticle

Kok Meng, Chan ; Rajab, Nor Fadilah ; Siegel, David ; Din, Laily Bin ; Ross, David ; Inayat-Hussain, Salmaan Hussain. / Goniothalamin induces coronary artery smooth muscle cells apoptosis : The p53-dependent caspase-2 activation pathway. In: Toxicological Sciences. 2010 ; Vol. 116, No. 2. pp. 533-548.
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