Journal Article

Goniothalamin Induces Coronary Artery Smooth Muscle Cells Apoptosis: The p53-Dependent Caspase-2 Activation Pathway

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

in Toxicological Sciences

Volume 116, issue 2, pages 533-548
Published in print August 2010 | ISSN: 1096-6080
Published online May 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq151
Goniothalamin Induces Coronary Artery Smooth Muscle Cells Apoptosis: The p53-Dependent Caspase-2 Activation Pathway

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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.

Keywords: goniothalamin; coronary artery smooth muscle cells; p53; NQO1; mitochondrial-mediated apoptosis; caspases

Journal Article.  8034 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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