Hypoxia Inhibits Cellular Senescence to Restore the Therapeutic Potential of Old Human Endothelial Progenitor Cells via the Hypoxia-Inducible Factor-1α–TWIST-p21 Axis

Lee, Sang Hun; Lee, Jun Hee; Yoo, So Young; Hur, Jin; Kim, Hyo–Soo; Kwon, Sang Mo

doi:10.1161/atvbaha.113.301931

Cited by 64 publications

(58 citation statements)

References 30 publications

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“…During hypoxia, EPCs are mobilized from the bone marrow into the peripheral blood and subsequently migrate to hypoxic tissues (2). Furthermore, hypoxia inhibits cellular senescence to restore the therapeutic potential of EPCs from elderly individuals (3). Therefore, EPCs may be developed as a promising novel treatment for ischemia/reperfusion injury.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

Zhou

Zeng

Xiong

2017

Experimental and Therapeutic Medicine

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Abstract. Endothelial progenitor cells (EPCs) participate in angiogenesis by differentiating into endothelial cells (ECs)and may be developed to treat ischemia/reperfusion injury. MicroRNAs (miRs) are a type of non-coding RNA that are 18-25 nucleotides in length and serve a role in angiogenesis. It has been demonstrated that miR-138 regulates hypoxia-induced EC dysfunction. However, to the best of our knowledge, the exact role of miR-138 in the regulation of hypoxia-induced EPCs has not previously been reported. In the present study, data collected from an MTT assay indicated that hypoxia treatment enhanced EPC proliferation, which was accompanied by an upregulation of hypoxia-inducible factor 1α (HIF-1α) expression. miR-138 overexpression inhibited hypoxia-induced EPC proliferation and induced cell cycle arrest at the G1 stage. A mechanistic investigation revealed that miR-138 negatively regulated HIF-1α protein levels but did not affect HIF-1α mRNA levels in EPCs. Moreover, results from a dual luciferase reporter assay demonstrated that HIF-1α was a direct target of miR-138 in EPCs. Furthermore, upregulation of miR-138 suppressed the hypoxia-induced upregulation of HIF-1α. Downstream factors of HIF-1α were also investigated and it was observed that the upregulation of miR-138 inhibited the hypoxia-induced upregulation of vascular endothelial growth factor, as well as the activity of mitogen-activated protein kinase and AKT signaling in EPCs. In summary, the present study suggested that miR-138 inhibits hypoxia-induced EPC proliferation, possibly by inhibiting HIF-1α-mediated signaling.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

Zhou

Zeng

Xiong

2017

Experimental and Therapeutic Medicine

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“…In the present study, hypoxia notably enhanced the proliferation of EPCs. Lee et al reported that hypoxia inhibits senescence of EPCs in aged humans (15). In addition, hypoxia/ischemia triggers EPCs to proceed from bone marrow into the peripheral blood, and EPCs can differentiate into ECs following migration into the site of hypoxia/ischemia in tissues (16).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces the proliferation of endothelial progenitor cells via upregulation of Apelin/APLNR/MAPK signaling

Zhang¹,

Liu²,

Fang³

et al. 2015

Molecular Medicine Reports

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Abstract. Endothelial progenitor cells (EPCs) can form new vessels through differentiation into endothelial cells (ECs), thus being important in the prevention of hypoxia/ischemia. Apelin can activate different signaling pathways through its receptor, APLNR, which regulate diverse biological functions, including cardiovascular function. However, the molecular mechanism by which Apelin mediates hypoxia-induced EPCs proliferation remain to be fully elucidated. The present study aimed to determine the role of Apelin/APLNR signaling in hypoxia-induced proliferation of EPCs. MTT assay was used to determine cell proliferation. Reverse transcription-quantitative polymerase chain reaction and western blotting analysis were conducted to examine mRNA and protein expression. It was revealed that hypoxia promoted the proliferation of the EPCs. Further investigation demonstrated that hypoxia promoted the expression levels of hypoxia-inducible factor (HIF)-1α, Apelin and APLNR in the EPCs. In addition, upregulation of Apelin or APLNR promoted the hypoxia-induced proliferation of the EPCs, while knockdown of Apelin or APLNR by small interfering RNA suppressed the hypoxia-induced proliferation of the EPCs, suggesting that the Apelin/APLNR axis is involved in hypoxia-induced proliferation of EPCs. Furthermore, pretreatment of the EPCs with SB-239063 or PD98059, two inhibitors of mitogen-activated protein kinase (MAPK), eliminated the Apelin upregulation-induced EPC proliferation, suggesting that MAPK signaling is a downstream effecter of Apelin/APLNR in EPCs. Therefore, the findings of the present study indicated that the production of HIF-1α, induced by hypoxia, activated the Apelin/APLNR and the downstream MAPK signaling pathways, leading to upregulated proliferation of the EPCs. These findings suggested that Apelin/APLNR signaling may be used as a potential therapeutic target for hypoxic/ischemic injury.

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“…TWIST1 cooperates with K-Ras G12D in lung tumorigenesis through suppressing key drivers of cell senescence such as p21 Cip1 , p16 INK4A /CDKN2A, and p27 Kip1 /CDKN1B (43). Sarcomas, derived from mesenchymal cells, as well as mesenchymal stem cells also display TWIST1 regulation of p21 Cip1 by both p53-dependent and -independent mechanisms (44-46). The inability of overexpressed TWIST1 to abrogate p21 Cip1 up-regulation as a result of FOXD3 expression in A375 cells may be associated with the high p53 steady state levels in these cells (Supplementary Figure S2B).…”

Section: Discussionmentioning

confidence: 99%

FOXD3 Modulates Migration through Direct Transcriptional Repression of TWIST1 in Melanoma

Weiss

Abel

Dadpey

et al. 2014

Molecular Cancer Research

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The neural crest is a multi-potent, highly migratory cell population that gives rise to diverse cell types, including melanocytes. Factors regulating the development of the neural crest and emigration of its cells are likely to influence melanoma metastasis. The transcription factor FOXD3 plays an essential role in pre-migratory neural crest development and has been implicated in melanoma cell dormancy and response to therapeutics. FOXD3 is down-regulated during migration of the melanocyte lineage from the neural crest, and our previous work supports a role for FOXD3 in suppressing melanoma cell migration and invasion. Alternatively, TWIST1 is known to have pro-migratory and pro-invasive roles in a number of cancers, including melanoma. Utilizing ChIP-seq analysis, TWIST1 was identified as a potential transcriptional target of FOXD3. Mechanistically, FOXD3 directly binds to regions of the TWIST1 gene locus, leading to transcriptional repression of TWIST1 in human mutant BRAF melanoma cells. Additionally, depletion of endogenous FOXD3 promotes up-regulation of TWIST1 transcript and protein. Finally, FOXD3 expression leads to a significant decrease in cell migration that can be efficiently reversed by the overexpression of TWIST1. These findings uncover the novel interplay between FOXD3 and TWIST1, which is likely to be important in the melanoma metastatic cascade.

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Hypoxia Inhibits Cellular Senescence to Restore the Therapeutic Potential of Old Human Endothelial Progenitor Cells via the Hypoxia-Inducible Factor-1α–TWIST-p21 Axis

Cited by 64 publications

References 30 publications

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

Hypoxia induces the proliferation of endothelial progenitor cells via upregulation of Apelin/APLNR/MAPK signaling

FOXD3 Modulates Migration through Direct Transcriptional Repression of TWIST1 in Melanoma

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