20(S)-Ginsenoside Rg3 prevents endothelial cell apoptosis via inhibition of a mitochondrial caspase pathway

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Abstract

Ginseng, refering to the roots of the species of the genus Panax ginseng, has been widely used in traditional oriental medicine for its wide spectrum of medicinal effects, such as anti-inflammatory, anti-tumorigenic, adaptogenic, and anti-aging activities. Many of its medicinal effects are attributed to the triterpene glycosides known as ginsenosides. In this study, we report a novel anti-apoptotic activity of 20(S)-ginsenoside Rg3 ((20S)Rg3) and its underlying molecular mechanism in human endothelial cells (ECs). ECs undergo apoptosis associated with increased LEHDase (caspase-9) and DEVDase (caspase-3) activity and DNA fragmentation after 24 h of serum deprivation. These apoptotic markers were suppressed by the addition of (20S)Rg3. (20S)Rg3 increased the expression of Bax and conversely decreased Bcl-2. (20S)Rg3 potently induced a rapid and sustained Akt activation and Bad phosphorylation, resulting in the inhibition of mitochondrial cytochrome c release. These anti-apoptotic activities of (20S)Rg3 were significantly abrogated in cells expressing dominant negative Akt. Taken together, our results suggest that (20S)Rg3 prevents EC apoptosis via Akt-dependent inhibition of the mitochondrial apoptotic signaling pathway. The novel property of (20S)Rg3 may be valuable for developing new pharmaceutical means that will control unwanted endothelial cell death at the site of vascular injury.

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Materials and methods

Materials. M199, penicillin, and streptomycin were purchased from LifeTechnologies (Grand Island, NY). N-acetyl-Asp-Glu-Val-Asp-p-nitroanilide (Ac-DEVD-pNA), N-acetyl-Ile-Glu-Thr-Asp-p-nitroanilide (Ac-IETD-pNA), and N-acetyl-Leu-Glu-His-Asp-p-nitroanilide (Ac-LEHD-pNA) were from Alexis Corporation (San Diego, CA). Wortmannin and PP1 were from BIOMOL (Plymouth Meeting, PA). Cytochrome c antibody was obtained from Pharmingen (San Diego, CA) and antibodies for caspase-3, caspase-8, caspase-9,

(20S)Rg3 protects endothelial cells from serum-deprived apoptosis

Serum and growth factor deprivation induces apoptosis in several cell types, including ECs [22]. We compared the effects of 20(R)- and 20(S)-ginsenoside Rg3 epimers (abbreviated as (20R)Rg3 and (20S)Rg3, respectively) on serum deprivation-induced HUVEC death with those of ginsenosides Rg1 and Rb1, which are main ingredients of white ginseng. Both Rg1 and Rb1 up to 10 μg/ml did not show any significant effect and (20R)Rg3 slightly inhibited EC death at 10 μg/ml (Fig. 1B). However, (20S)Rg3

Discussion

Ginsenosides possess triterpene structure in the backbone and have a structural diversity. So far, 35 kinds of ginsenosides have been isolated from fresh, white or red ginseng, among which 22 kinds of ginsenosides are protopanaxadiol type and 12 of them are protopanaxatriol type, and only one ginsenoside Ro is oleanane type [28]. Since ginsenosides are generally labile under acidic condition, the chemical transformation of secondary metabolites occurrs during the preparative processes for red

Acknowledgments

This work was supported by research Grant (M10416130002-04N1613-00210) from Korea Biotech R&D Group of MoST, Grant (R02-2003-000-10041-0) from the Korean Government (MOEHRD) of MoST, and Vascular System Research Center Grant from KOSEF.

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