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Novel Regulators of Endothelial Progenitor Cell Homing and Differentiation
Kwon, Young-Guen 이화여자대학교 세포신호전달연구센터 2008 고사리 세포신호전달 심포지움 Vol. No.10
Endothelial progenitor cells(EPC) contribute to the formation of vascular networks during embryonic development and also to neovascularization in settings of tissue ischemia or tumors in postnatal life. However, the molecular mechanisms by which EPCs incorporate at a neovascular zone and differentiate into endothelial cells are rarely identified. In this study, we show that insulin-like growth factor 2(IGF2), which has a comparable activity with stromal cell-derived factor-1, is a prominent homing factor for EPCs. The IGF2/mannose-6 phosphate receptor(IGF2R) is highly expressed in EPCs isolated from human cord blood and CD34^(+) mononuclear cells from mouse bone marrow(BMMNCs), whereas IGF2 was not present in these cells. IGF2 enhanced the chemotaxis, adhesion, invasion and MMP9 expression of EPCs in an IGF2R-dependent manner. Moreover, tumor cells and ECs increased IGF2 expression under hypoxia and conditioned media from these cultured cells increased EPC chemotaxis. All these effects of IGF2 were sensitive to inhibitors of G(i) protein, phospholipase C(PLC), and intracellular calcium mobilization, suggesting a significant role for the G(i)-PLC-Ca^(2+) pathway in the functions of IGF2. Consistent with this interpretation, EPCs specifically expressed the β2 isoform of PLC and knockdown of this protein by siRNA significantly abrogated the responses of EPCs to IGF2. Finally, IGF2 enhanced recruitment of CD34^(+) BMMNCs into the retinal blood vessels of mice and newly formed blood vessels in implanted Matrigel plugs. These findings indicate that locally generated IGF2 at ischemic or tumor sites may contribute to postnatal vasculogenesis by augmenting the recruitment of EPCs and systematic activation of the IGF2/IGF2R axis may be a useful means for therapeutic neovascularization.
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.
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.