Urotensin II promotes the proliferation of endothelial progenitor cells through p38 and p44/42 MAPK activation

Xu, Shixin; Wen, Huazhi; Jiang, Hong

doi:10.3892/mmr.2012.899

Cited by 6 publications

(4 citation statements)

References 17 publications

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“…The regulation of apoptosis in endothelial cells is critical for the integrity of endothelium. Studies also found that U-II promote the proliferation of rat bone marrow-derived EPCs through a process that involves ERK activation [29] . In our study, we examined the potential inhibited apoptosis function of U-II in HUVEC and the role of PI3K/Akt and ERK signaling in this process.…”

Section: Discussionmentioning

confidence: 98%

Urotensin II Inhibits Doxorubicin-Induced Human Umbilical Vein Endothelial Cell Death by Modulating ATF Expression and via the ERK and Akt Pathway

et al. 2014

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Background and PurposeRegulation of the homeostasis of vascular endothelium is critical for the processes of vascular remodeling and angiogenesis under physiological and pathological conditions. Urotensin II (U-II), a potent vasoactive peptide, participates in vascular and myocardial remodeling after injury. We investigated the protective effect of U-II on doxorubicin (DOX)-induced apoptosis in cultured human umbilical vein endothelial cells (HUVECs) and the potential mechanisms involved in this process.Experimental ApproachCultured HUVECs were treated with vehicle, DOX (1 µM), U-II, or U-II plus DOX. Apoptosis was evaluated by DNA strand break level with TdT-mediated dUTP nick-end labeling (TUNEL) staining. Western blot analysis was employed to determine the related protein expression and flow cytometry assay was used to determine the TUNEL positive cells.Key ResultsU-II reduced the quantity of cleaved caspase-3 and cytosol cytochrome c and increased Bcl-2 expression, which results in protecting HUVECs from DOX-induced apoptosis. U-II induced Activating transcription factor 3 (ATF3) at both mRNA and protein levels in U-II-treated cells. Knockdown of ATF3 with ATF3 siRNA significantly reduced ATF3 protein levels and U-II protective effect under DOX-treated condition. U-II downregulated p53 expression in DOX-induced HUVECs apoptosis, and it rapidly activated extracellular signal-regulated protein kinase (ERK) and Akt. The DOX induced change of p53 was not affected by U-II antagonist (urantide) under ATF-3 knockdown. The inhibitory effect of U-II on DOX-increased apoptosis was attenuated by inhibitors of ERK (U0126) and PI3K/Akt (LY294002).Conclusion and ImplicationsOur observations provide evidence that U-II protects HUVECs from DOX-induced apoptosis. ERK-Akt phosphorylation, ATF3 activation, and p53 downregulation may play a signal-transduction role in this process.

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Section: Discussionmentioning

confidence: 98%

Urotensin II Inhibits Doxorubicin-Induced Human Umbilical Vein Endothelial Cell Death by Modulating ATF Expression and via the ERK and Akt Pathway

et al. 2014

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“…Several signaling pathways have been implicated in the induction of IL-8 expression, including nuclear factor- κ B (NF- κ B)- and activating protein (AP)-1-dependent pathway which are activated by mitogen-activated protein kinases (MAPKs) pathway, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK pathway in endothelial cells [10] , [11] . In addition, U-II has been shown to activate MAPK signal transduction pathways in different cell types [12] – [14] . Although U-II has been found to induce the proliferation of endothelial cells [6] , its induction of IL-8 gene expression in vascular endothelial cells has not been studied, and the crosstalk between U-II and IL-8 in activation of endothelial cells remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Urotensin II Induces Interleukin 8 Expression in Human Umbilical Vein Endothelial Cells

et al. 2014

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BackgroundUrotensin II (U-II), an 11-amino acid peptide, exerts a wide range of actions in cardiovascular systems. Interleukin-8 (IL-8) is secreted by endothelial cells, thereby enhancing endothelial cell survival, proliferation, and angiogenesis. However, the interrelationship between U-II and IL-8 as well as the detailed intracellular mechanism of U-II in vascular endothelial cells remain unclear. The aim of this study was to investigate the effect of U-II on IL-8 expression and to explore its intracellular mechanism in human umbilical vein endothelial cells.Methods/Principal FindingsPrimary human umbilical vein endothelial cells were used. Expression of IL-8 was determined by real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and luciferase reporter assay. Western blot analyses and experiments with specific inhibitors were performed to reveal the downstream signaling pathways as concerned. U-II increased the mRNA/protein levels of IL-8 in human umbilical vein endothelial cells. The U-II effects were significantly inhibited by its receptor antagonist [Orn5]-URP. Western blot analyses and experiments with specific inhibitors indicated the involvement of phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase in U-II-induced IL-8 expression. Luciferase reporter assay further revealed that U-II induces the transcriptional activity of IL-8. The site-directed mutagenesis indicated that the mutation of AP-1 and NF-kB binding sites reduced U-II-increased IL-8 promoter activities. Proliferation of human umbilical vein endothelial cells induced by U-II could be inhibited significantly by IL-8 RNA interference.Conclusion/SignificanceThe results show that U-II induces IL-8 expression in human umbilical vein endothelial cells via p38 mitogen-activated protein kinase and extracellular signal-regulated kinase signaling pathways and IL-8 is involved in the U-II-induced proliferation of human umbilical vein endothelial cells.

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“…EPCs are pluripotent stem cells, which have the potential to differentiate into mature endothelial cells ( 37 ). However, the exact role of the SDF-1α/CXCR4 signaling pathway in EPC-mediated angiogenesis in osteosarcomas remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Melittin inhibits tumor angiogenesis modulated by endothelial progenitor cells associated with the SDF-1α/CXCR4 signaling pathway in a UMR-106 osteosarcoma xenograft mouse model

Qin

Chen

et al. 2016

Molecular Medicine Reports

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Endothelial progenitor cells (EPCs) are important in tumor angiogenesis. Stromal cell-derived factor-1α (SDF-1α) and its receptor C-X-C chemokine receptor type 4 (CXCR4) are key in stem cell homing. Melittin, a component of bee venom, exerts antitumor activity, however, the underlying mechanisms remain to be elucidated. The present study aimed to assess the effects of melittin on EPCs and angiogenesis in a mouse model of osteosarcoma. UMR-106 cells and EPCs were treated with various concentrations of melittin and cell viability was determined using the MTT assay. EPC adherence, migration and tube forming ability were assessed. Furthermore, SDF-1α, AKT and extracellular signal-regulated kinase (ERK)1/2 expression levels were detected by western blotting. Nude mice were inoculated with UMR-106 cells to establish an osteosarcoma mouse model. The tumors were injected with melittin, and its effects were assessed by immunohistochemistry and immunofluorescence. Melittin decreased the viability of UMR-106 cells and EPCs. In addition, it decreased EPC adhesion, migration and tube formation when compared with control and SDF-1α-treated cells. Melittin decreased the expression of phosphorylated (p)-AKT, p-ERK1/2, SDF-1α and CXCR4 in UMR-106 cells and EPCs when compared with the control. The proportions of cluster of differentiation (CD)34/CD133 double-positive cells were 16.4±10.4% in the control, and 7.0±4.4, 2.9±1.2 and 1.3±0.3% in tumors treated with 160, 320 and 640 µg/kg melittin per day, respectively (P<0.05). At 11 days, melittin reduced the tumor size when compared with that of the control (control, 4.8±1.3 cm3; melittin, 3.2±0.6, 2.6±0.5, and 2.0±0.2 cm3 for 160, 320 and 640 µg/kg, respectively; all P<0.05). Melittin decreased the microvessel density, and SDF-1α and CXCR4 protein expression levels in the tumors. Melittin may decrease the effect of osteosarcoma on EPC-mediated angiogenesis, possibly via inhibition of the SDF-1α/CXCR4 signaling pathway.

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Urotensin II promotes the proliferation of endothelial progenitor cells through p38 and p44/42 MAPK activation

Cited by 6 publications

References 17 publications

Urotensin II Inhibits Doxorubicin-Induced Human Umbilical Vein Endothelial Cell Death by Modulating ATF Expression and via the ERK and Akt Pathway

Urotensin II Inhibits Doxorubicin-Induced Human Umbilical Vein Endothelial Cell Death by Modulating ATF Expression and via the ERK and Akt Pathway

Urotensin II Induces Interleukin 8 Expression in Human Umbilical Vein Endothelial Cells

Melittin inhibits tumor angiogenesis modulated by endothelial progenitor cells associated with the SDF-1α/CXCR4 signaling pathway in a UMR-106 osteosarcoma xenograft mouse model

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