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Kim, Young-Mi,Namkoong, Seung,Yun, Young-Gab,Hong, Hee-Do,Lee, Young-Chul,Ha, Kwon-Soo,Lee, Hansoo,Kwon, Ho Jeong,Kwon, Young-Guen,Kim, Young-Myeong Pharmaceutical Society of Japan 2007 BIOLOGICAL & PHARMACEUTICAL BULLETIN Vol.30 No.9
<P>Angiogenesis is important for promoting cardiovascular disease, wound healing, and tissue regeneration. We investigated the effects of Korean red ginseng water extract (KRGE) on angiogenesis and its underlying signal mechanism. KRGE increased <I>in vitro</I> proliferation, migration, and tube formation of human umbilical vein endothelial cells, as well as stimulated <I>in vivo</I> angiogenesis without increasing VEGF expression. KRGE-induced angiogenesis was accompanied by phosphorylation of ERK1/2, phosphatidylinositol 3-kinase (Akt), and endothelial nitric oxide synthase (eNOS) as well as an increase in NO production. Inhibition of PI3K activity by wortmannin completely inhibited KRGE-induced angiogenesis and phosphorylation of Akt, ERK1/2, and eNOS, indicating that PI3K/Akt activation is an upstream event of the KRGE-mediated angiogenic pathway. The MEK inhibitor PD98059 blocked KRGE-induced ERK1/2 phosphorylation without affecting Akt and eNOS activation. However, the eNOS inhibitor <I>N</I><SUP>G</SUP>-monomethyl-<SMALL>L</SMALL>-arginine effectively inhibited tube formation, but partially blocked proliferation and migration as well as ERK phosphorylation, without altering Akt and eNOS activation, revealing that the eNOS/NO pathway is partially involved in ERK1/2 activation. This study demonstrated that KRGE stimulates <I>in vitro</I> and <I>in vivo</I> angiogenesis through the activation of the PI3K/Akt-dependent ERK1/2 and eNOS signal pathways and their cross talk.</P>
Young-Mi Kim,Jung Hwan Kim,Hyuk Min Kwon,Dong Heon Lee,Moo-Ho Won,Young-Guen Kwon,Young-Myeong Kim 고려인삼학회 2013 Journal of Ginseng Research Vol.37 No.4
Korean Red Ginseng extract (KRGE) is a traditional herbal medicine utilized to prevent endothelium dysfunction in the cardiovascular system; however, its underlying mechanism has not been clearly elucidated. We here examined the pharmacological effect and molecular mechanism of KRGE on apoptosis of human umbilical vein endothelial cells (HUVECs) in a serum-deprived apoptosis model. KRGE protected HUVECs from serum-deprived apoptosis by inhibiting mitochondrial cytochrome c release and caspase-9/-3 activation. This protective effect was significantly higher than that of American ginseng extract. KRGE treatment increased antiapoptotic Bcl-2 and Bcl-XL protein expression and Akt-dependent Bad phosphorylation. Moreover, KRGE prevented serum deprivation-induced subcellular redistribution of these proteins between the mitochondrion and the cytosol, resulting in suppression of mitochondrial cytochrome c release. In addition, KRGE increased nitric oxide (NO) production via Akt-dependent activation of endothelial NO synthase (eNOS), as well as inhibited caspase-9/-3 activities. These increases were reversed by co-treatment of cells with inhibitors of eNOS and phosphoinositide 3-kinase (PI3K) and pre-incubation of cell lysates in dithiothreitol, indicating KRGE induces NO-mediated caspase modification. Indeed, KRGE inhibited caspase-3 activity via S-nitrosylation. These findings suggest that KRGE prevents serum deprivation-induced HUVEC apoptosis via increased Bcl-2 and Bcl-XL protein expression, PI3K/Akt-dependent Bad phosphorylation, and eNOS/NO-mediated S-nitrosylation of caspases. The cytoprotective property of KRGE may be valuable for developing new pharmaceutical means that limit endothelial cell death induced during the pathogenesis of vascular diseases.
Regulation of Apoptosis Signaling by Nitrosative Stress
Kwon, Young-Guen,Kim, Young-Myeong 이화여자대학교 세포신호전달연구센터 2002 고사리 세포신호전달 심포지움 Vol. No.4
Nitrosative stress that occurs via S-nitrosylation by interaction of nitric oxide(NO) with the biological thiols of proteins with nitric oxide(NO), synthesized from L-arginine by catalytic reaction of three isoforms of NO synthases, can regulate apoptosis. The reaction induces the decreased cellular redox potential, inhibition of metabolic enzymes, and regulation of gene expression. Caspase family, containing thiol residue in their catalytic sites, is a key enzyme in apoptotic cell death. These enzymes are activated in cells treated with cytotoxic cytokine such as TNFα, TRAIL, or Fas and then induce apoptotic cell death. The cysteine residue of the caspase protease is well-known target site for the redox-based modification S-nitrosylation. NO has been known to be either an inducer of apoptosis in some cells or inhibitor of apoptosis in others. We investigated the role of NO in apoptotic cell death and caspase activation/activity of hepatocytes and macrophage cell line RAW264.7 cells. Treatment with TNFα-induced apoptotic cell death accompanied by DNA fragmentation and caspase activation in cultured hepatocytes. The increased enzyme activation/activity was correlated with cleavage of Bcl-2 and Bid and mitochondrial cytochrome c release, which is a mediator of further activation of caspase-9 via the formation of apoptosome. NO(produced by NO donor SNAP and cytokine-mediated iNOS induction) and caspase inhibitors(Ac-DEVD-cho and Z-VAD-fmk) inhibited hepatocyte apoptosis, caspase activity, cleavage of Bcl-2 family, and cytochrome c release. Treatment of recombinant 7 members of caspase family with SNAP inhibited their catalytic activity by redox-based S-nitrosylation. These results indicate that NO can protect hepatocytes from TNFα-induced apoptosis. However, we found that SNAP treatment induced apoptotic cell death with DNA fragmentation, caspase activation, and cytochrome c release in RAW264.7 cells(low iron content), but not in hepatocytes(high iron). When increasing the cellular non-heme iron level in RAW264.7 cells pretreated with FeSO₄, the cells induced the resistant against SNAP-induced apoptosis, formation of dinirosyl-iron complexes(DNIC), suppression of caspase activation/activity, and cytochrome c release. Furthermore, synthetic DNIC showed the inhibitory effect on caspase-3 activity in vitro by S-nitrosylation. These data concluded that cellular non-heme iron content is a determinant of NO-mediated apoptosis and caspase inhibition.