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Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1? to promote angiogenesis.

ABSTRACT: Hypoxia-inducible factor (HIF-1) is the key transcription regulator for multiple angiogenic factors and is an appealing target. Ginsenoside-Rg1, a nontoxic saponin isolated from the rhizome of Panax ginseng, exhibits potent proangiogenic activity and has the potential to be developed as a new angiotherapeutic agent. However, the mechanisms by which Rg1 promotes angiogenesis are not fully understood. Here, we show that Rg1 is an effective stimulator of HIF-1? under normal cellular oxygen conditions in human umbilical vein endothelial cells. HIF-1? steady-state mRNA was not affected by Rg1. Rather, HIF-1? protein synthesis was stimulated by Rg1. This effect was associated with constitutive activation of phosphatidylinositol 3-kinase (PI3K)/Akt and its effector p70 S6 kinase (p70(S6K)), but not extracellular-signal regulated kinase 1/2. We further revealed that HIF-1? induction triggered the expression of target genes, including vascular endothelial growth factor (VEGF). The use of small molecule inhibitors LY294002 or rapamycin to inhibit PI3K/Akt and p70(S6K) activities, respectively, resulted in diminished HIF-1? activation and subsequent VEGF expression. RNA interference-mediated knockdown of HIF-1? suppressed Rg1-induced VEGF synthesis and angiogenic tube formation, confirming that the effect was HIF-1? specific. Similarly, the angiogenic phenotype could be reversed by inhibition of PI3K/Akt and p70(S6K). These results define a hypoxia-independent activation of HIF-1?, uncovering a novel mechanism for Rg1 that could play a major role in angiogenesis and vascular remodeling.

SUBMITTER: Leung KW

PROVIDER: S-EPMC3214261 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis.

Leung Kar-Wah KW Ng Hoi-Man HM Tang Maggie K S MK Wong Chris C K CC Wong Ricky N S RN Wong Alice S T AS

Angiogenesis 20111002 4

Hypoxia-inducible factor (HIF-1) is the key transcription regulator for multiple angiogenic factors and is an appealing target. Ginsenoside-Rg1, a nontoxic saponin isolated from the rhizome of Panax ginseng, exhibits potent proangiogenic activity and has the potential to be developed as a new angiotherapeutic agent. However, the mechanisms by which Rg1 promotes angiogenesis are not fully understood. Here, we show that Rg1 is an effective stimulator of HIF-1α under normal cellular oxygen conditio ...[more]

PMID: 21964931

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Project description:Accumulation of hypoxia inducible factor-1α (HIF-1α) is commonly an acute and beneficial response to hypoxia, whereas chronically elevated HIF-1α is associated with multiple disease conditions, including preeclampsia, a serious hypertensive disease of pregnancy. However, the molecular basis underlying the persistent elevation of placental HIF-1α in preeclampsia and its role in the pathogenesis of preeclampsia are poorly understood. Here we report that Hif-1α mRNA and HIF-1α protein were elevated in the placentas of pregnant mice infused with angiotensin II type I receptor agonistic autoantibody, a pathogenic factor in preeclampsia. Knockdown of placental Hif-1α mRNA by specific siRNA significantly attenuated hallmark features of preeclampsia induced by angiotensin II type I receptor agonistic autoantibody in pregnant mice, including hypertension, proteinuria, kidney damage, impaired placental vasculature, and elevated maternal circulating soluble fms-like tyrosine kinase-1 levels. Next, we discovered that Hif-1α mRNA levels and HIF-1α protein levels were induced in an independent preeclampsia model with infusion of the inflammatory cytokine tumor necrosis factor superfamily member 14 (LIGHT). SiRNA knockdown experiments also demonstrated that elevated HIF-1α contributed to LIGHT-induced preeclampsia features. Translational studies with human placentas showed that angiotensin II type I receptor agonistic autoantibody or LIGHT is capable of inducing HIF-1α in a hypoxia-independent manner. Moreover, increased HIF-1α was found to be responsible for angiotensin II type I receptor agonistic autoantibody or LIGHT-induced elevation of Flt-1 gene expression and production of soluble fms-like tyrosine kinase-1 in human villous explants. Overall, we demonstrated that hypoxia-independent stimulation of HIF-1α gene expression in the placenta is a common pathogenic mechanism promoting disease progression. Our findings reveal new insight to preeclampsia and highlight novel therapeutic possibilities for the disease.

Dataset Information

Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1? to promote angiogenesis.

Publications

Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis.

Similar Datasets

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