Ginsenoside Rg3 disrupts actin-cytoskeletal integrity leading to contractile dysfunction and apoptotic cell death in vascular smooth muscle

• Published in: Food and chemical toxicology 2018-08, Vol.118, p.645-652
• Main Authors: Jung, Yeryeon, Kim, Keunyoung, Bian, Yiying, Ngo, Thien, Bae, Ok-Nam, Lim, Kyung-Min, Chung, Jin-Ho
• Format: Article
• Language: English
• Subjects: Actin cytoskeleton; Actin-targeting anti-cancer agents; Apoptosis; Ginseng; Ginsenoside Rg3; Vascular toxicity
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2018.06.015

Ginseng and its major active ingredients, ginsenosides are widely consumed for various health benefits including the prevention or treatment of cancer without any special precaution. Previously, we demonstrated that Rg3, one of ginsenosides with a potent anti-cancer activity, may cause contractile dysfunction, and structural damage against normal vascular smooth muscle through apoptotic cell death. However, mechanism underlying the vascular toxicity of Rg3 was not fully elucidated. Here we demonstrated that the vascular toxicity of Rg3 occurs through actin disruption and Bmf-initiated mitochondrial apoptotic pathway, the mechanism which may be shared with its anti-cancer effects. In normal rat primary vascular smooth muscle cells, Rg3 induced apoptosis and contractile dysfunction as determined by caspase-3 activation, TUNEL staining, and insufficient myosin light chain phosphorylation. Rg3 induced actin degradation with RhoA inactivation, followed by mitochondrial translocation of Bmf and dissociation of mitochondrial membrane potential (φ). Pre-treatment of jasplakinolide, an inhibitor of actin depolymerization, significantly blocked Rg3-induced φ dissipation and apoptosis. Notably, Rg3 also induced actin disruption in hepatoma cell line, HepG2, which was reversed by jasplakinolide, confirming that the anti-cancer effects of Rg3 shares the mechanism at least in part. Collectively, these results demonstrated that Rg3 may induce vascular toxicity as well as anti-cancer effects through disrupting actin, suggesting the potential toxicity associated with inadvertent use of ginseng and its products. [Display omitted] •Ginsenoside Rg3 induced apoptosis and contractile dysfunction in vascular smooth muscle cell.•This events were mediated through actin-disruption and subsequent activation of Bmf-initiated apoptosis.•Rg3 disrupted actin filaments in hepatoma cell line as well.•The anti-cancer effects of Rg3 shares the toxic mechanism in normal vascular smooth muscles.