Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells

Chung, Byung Hee; Kim, Jong Dai; Kim, Chun Ki; Kim, Jung-whan; Won, Moo Ho; Lee, Han Soo; Dong, Mi Sook; Ha, Kwon Soo; Kwon, Young Geun; Kim, Young Myeong

doi:10.1016/j.bbrc.2008.09.001

Cited by 150 publications

(124 citation statements)

References 21 publications

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“…Additionally, icariin at the dose used did not cause noticeable toxicity to the liver. Icariin is a flavonol glycoside purified from plants of the genus Epimedium (45), and previous studies have documented that it has multiple functions which include roles in reducing oxidative stress, limiting apoptosis, protecting the cardiovascular system and promoting angiogenesis (46)(47)(48)(49). The present study is the first, to the very best of our knowledge, to reveal that icariin regulates iron metabolism by modulating hepcidin expression.…”

Section: Discussionmentioning

confidence: 54%

Icariin regulates systemic iron metabolism by increasing hepatic hepcidin expression through Stat3 and Smad1/5/8 signaling

Zhang

Liu

Guo

et al. 2016

International Journal of Molecular Medicine

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Abstract. Systemic iron homeostasis is strictly controlled under normal conditions to ensure a balance between the absorption, utilization, storage and recycling of iron. The hepcidin-ferroportin (FPN) axis is of critical importance in the maintenance of iron homeostasis. Hepcidin deficiency gives rise to enhanced dietary iron absorption, as well as to increased iron release from macrophages, and this in turn results in iron accumulation in the plasma and organs, and is associated with a range of tissue pathologies. Low hepcidin levels have been demonstrated in most forms of hereditary hemochromatosis (HH), as well as in β-thalassemia. Therapies that increase hepcidin concentrations may potentially play a role in the treatment of these iron overload-related diseases. To date, natural compounds have not been extensively investigated for this purpose, to the best of our knowledge. Thus, in the present study, we screened natural compounds that have the potential to regulate hepcidin expression. By performing hepcidin promoter-luciferase assay, RT-qPCR and animal experiments, we demonstrated that icariin and berberine were potent stimulators of hepcidin transcription.Mechanistic experiments indicated that icariin and berberine increased hepcidin expression by activating the signal transducer and activator of transcription 3 (Stat3) and Smad1/5/8 signaling pathways. The induction of hepcidin was confirmed in mice following icariin administration, coupled with associated changes in serum and tissue iron concentrations. In support of these findings, the icariin analogues, epimedin A, B and C, also increased hepatic hepcidin expression. However, these changes were not observed in hepcidin-deficient [Hamp1 -/-or Hamp1-knockout (KO)] mice following icariin administration, thereby verifying hepatic hepcidin as the target of icariin. Although berberine exhibited a robust capacity to promote hepcidin expression in vitro, it failed to alter hepcidin expression in mice. Taken together, the findings of the present study suggest that icariin exhibits a robust capacity to increase hepatic hepcidin expression and to modulate systemic iron homeostasis. The present study therefore highlights the significance of using natural compounds to ameliorate iron disorders through the regulation of hepcidin expression. IntroductionIron is an essential metal involved in a large array of biological processes, such as energy metabolism, DNA replication and other important cellular functions (1-3). Systemic iron homeostasis is accurately and strictly governed to ensure a balance between iron absorption, utilization and storage in mammals (4). Hepcidin is the central hormone secreted by hepatocytes that plays a fundamental role in the regulation of iron flow through limiting dietary iron absorption from the duodenum and reducing iron egress from macrophages (5). Hepcidin achieves this effect by binding to its receptor, ferroportin (FPN; the only known iron exporter thus far), on the plasma membrane of target cells and inducing its internalization ...

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Section: Discussionmentioning

confidence: 54%

Icariin regulates systemic iron metabolism by increasing hepatic hepcidin expression through Stat3 and Smad1/5/8 signaling

Zhang

Liu

Guo

et al. 2016

International Journal of Molecular Medicine

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“…These results suggested that the effects of HANPs on HUVEC function do not exert by the modulation of VEGF expression, indicating HANPs may act as a direct negative regulator of ECs. Synthesis of NO, under the regulation of the eNOS, 16,17 plays an essential role in the maintenance of EC homeostasis, reparative vasculogenesis and postnatal angiogenesis. 21,52,53 In this context, we investigated whether NO might participate in the influence of HAPNs on ECs.…”

Section: Discussionmentioning

confidence: 99%

“…However, in spite of their use as bone substitute, our understanding of the effects of nano-HAP on ECs remains fragmentary. Recently, the production of nitric oxide (NO) through eNOS activation 16,17 has often been reported as a mechanism of the growth of ECs, 18 apoptosis, 19 migration 18,20 and angiogenesis, 21 suggesting a potential role of NO in changes of biological behavior in ECs. Previous studies have shown that NO activation was involved in porous β-CaSiO 3 /Poly-D,L-LactideGlycolide (PDLGA) composite scaffold-induced increased angiogenic activity of ECs.…”

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confidence: 99%

Interaction of hydroxyapatite nanoparticles with endothelial cells: internalization and inhibition of angiogenesis in vitro through the PI3K/Akt pathway

Shi¹,

Zhou²,

Huang³

et al. 2017

IJN

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Nano-hydroxyapatite (nano-HAP) has been proposed as a better candidate for bone tissue engineering; however, the interactions of nano-HAP with endothelial cells are currently unclear. In this study, HAP nanoparticles (HANPs; 20 nm np20 and 80 nm np80) and micro-sized HAP particles (m-HAP; 12 μm) were employed to explore and characterize cellular internalization, subcellular distribution, effects of HANPs on endothelial cell function and underlying mechanisms using human umbilical vein endothelial cells (HUVECs) as an in vitro model. It was found that HANPs were able to accumulate in the cytoplasm, and both adhesion and uptake of the HANPs followed a function of time; compared to np80, more np20 had been uptaken at the end of the observation period. HANPs were mainly uptaken via clathrin- and caveolin-mediated endocytosis, while macropinocytosis was the main pathway for m-HAP uptake. Unexpectedly, exposure to HANPs suppressed the angiogenic ability of HUVECs in terms of cell viability, cell cycle, apoptosis response, migration and capillary-like tube formation. Strikingly, HANPs reduced the synthesis of nitric oxide (NO) in HUVECs, which was associated with the inhibition of phosphatidylinositol 3-kinase (PI3K) and phosphorylation of eNOS. These findings provide additional insights into specific biological responses as HANPs interface with endothelial cells.

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“…37 Further, icariin stimulated myocardial cell differentiation by the generation of reactive oxygen species, which increased p38MAPK levels. 38 Chung et al 39 found that Figure 4 Morphological analysis of autophagy in the smooth muscle cells (SMCs) from each group. (a) Punctate autophagosomes were observed using transmission electron microscopy monodansylcadaverine staining and GFP-LC3 transfection localisation methods.…”

Section: Discussionmentioning

confidence: 99%

Effect of icarisid II on diabetic rats with erectile dysfunction and its potential mechanism via assessment of AGEs, autophagy, mTOR and the NO–cGMP pathway

Zhang¹,

Li²,

Liu³

et al. 2012

Asian J Androl

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Erectile dysfunction (ED) is a major complication of diabetes mellitus. Icariin has been shown to enhance erectile function through its bioactive form, icarisid II. This study investigates the effects of icarisid II on diabetic rats with ED and its potential mechanism via the assessment of advanced glycosylation end products (AGEs), autophagy, mTOR and the NO-cGMP pathway. Icarisid II was extracted from icariin by an enzymatic method. In the control and diabetic ED groups, rats were administered normal saline; in the icarisid II group, rats were administered icarisid II intragastrically. Erectile function was evaluated by measuring intracavernosal pressure/mean arterial pressure (ICP/MAP). AGE concentrations, nitric oxide synthase (NOS) activity and cGMP concentration were assessed by enzyme immunoassay. Cell proliferation was analysed using methyl thiazolyl tetrazolium assay and flow cytometry. Autophagosomes were observed by transmission electron microscopy, monodansylcadaverine staining and GFP-LC3 localisation. The expression of NOS isoforms and key proteins in autophagy were examined by western blot. Our results have shown that Icarisid II increased ICP/MAP values, the smooth muscle cell (SMC) growth curve, S phase and SMC/collagen fibril (SMC/CF) proportions and decreased Beclin 1 (P,0.05). Icarisid II significantly increased the proliferative index and p-p70S6K(Thr389) levels and decreased the numbers of autophagosomes and the levels of LC3-II (P,0.01). Icarisid II decreased AGE concentrations and increased cGMP concentration, NOS activity (P,0.05) and cNOS levels (P,0.01) in the diabetic ED group. Therefore, Icarisid II constitutes a promising compound for diabetic ED and might be involved in the upregulation of SMC proliferation and the NO-cGMP pathway and the downregulation of AGEs, autophagy and the mTOR pathway.

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Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells

Cited by 150 publications

References 21 publications

Icariin regulates systemic iron metabolism by increasing hepatic hepcidin expression through Stat3 and Smad1/5/8 signaling

Icariin regulates systemic iron metabolism by increasing hepatic hepcidin expression through Stat3 and Smad1/5/8 signaling

Interaction of hydroxyapatite nanoparticles with endothelial cells: internalization and inhibition of angiogenesis in vitro through the PI3K/Akt pathway

Effect of icarisid II on diabetic rats with erectile dysfunction and its potential mechanism via assessment of AGEs, autophagy, mTOR and the NO–cGMP pathway

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