Hyperglycemia Accelerated Endothelial Progenitor Cell Senescence via the Activation of p38 Mitogen-Activated Protein Kinase

Kuki, Shintaro; Imanishi, Toshio; Kobayashi, Katsunobu; Matsuo, Yoshiki; Obana, Masahiro; Akasaka, Takashi

doi:10.1253/circj.70.1076

Cited by 116 publications

(87 citation statements)

References 41 publications

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“…Many upstream signals are reported to exert in cellular senescence, such as PI3K-Akt, p38 MAPK, and NF-jB signals [13][14][15]. We previously found that PI3K-Akt pathway inhibits the senescence of hSKPs while promoting their self-renewal [8].…”

Section: Introductionmentioning

confidence: 99%

Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27KIP1/p15INK4b signaling

Liu

Wang

Zhao

et al. 2015

Cell. Mol. Life Sci.

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Multipotent skin-derived precursors (SKPs) are dermal stem cells with the capacity to reconstitute the dermis and other tissues, such as muscles and the nervous system. Thus, the easily available human SKPs (hSKPs) hold great promises in regenerative medicine. However, long-term expansion is difficult for hSKPs in vitro. We previously demonstrated that hSKPs senesced quickly under routine culture conditions. To identify the underlying mechanisms so as to find an effective way to expand hSKPs, time-dependent microarray analysis of gene expression in hSKPs during in vitro culture was performed. We found that the senescence of hSKPs had a unique gene expression pattern that differs from reported typical senescence. Subsequent investigation ruled out the role of DNA damage and classical p53 and p16 INK4a signaling in hSKP senescence. Examination of cyclin-dependent kinase inhibitors revealed the involvement of p15 INK4b and p27 KIP1 . Further exploration about upstream signals indicated the contribution of Akt hypo-activity and FOXO3 to hSKP senescence. Forced activation of Akt and knockdown of FOXO3, p15 INK4b and p27 KIP1 effectively inhibited hSKP senescence and promoted hSKP proliferation. The unique senescent phenotype of human dermal stem cells and the role of Akt-FOXO3-p27 KIP1 /p15 INK4b signaling in regulating hSKP senescence provide novel insights into the senescence and self-renewal regulation of adult stem cells. The present study also points out a way to propagate hSKPs in vitro so as to fulfill their promises in regenerative medicine.

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Section: Introductionmentioning

confidence: 99%

Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27KIP1/p15INK4b signaling

Liu

Wang

Zhao

et al. 2015

Cell. Mol. Life Sci.

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“…Thus, NO could be critical to the regulation of EPC functions. Recently, it was demonstrated that hyperglycemia-induced impairment of early EPCs could be restored via the modulation of p38 mitogenactivated protein kinase (MAPK) (17,18) and Akt/FoxO1 signaling (19). However, the effects and mechanisms on late EPCs are not known.…”

mentioning

confidence: 99%

High Glucose Impairs Early and Late Endothelial Progenitor Cells by Modifying Nitric Oxide–Related but Not Oxidative Stress–Mediated Mechanisms

et al. 2007

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OBJECTIVE-Endothelial progenitor cells (EPCs) are impaired in diabetes. This study aimed to investigate the direct effects of high glucose on EPCs.RESEARCH DESIGN AND METHODS-Mononuclear cells isolated from healthy subjects were incubated with glucose/ mannitol or drugs for EPC study. After 4 days of culture, attached early EPCs appeared. The monolayer late EPCs with cobblestone shape appeared at 2-4 weeks. Various immunofluroscence stainings were used to characterize the early and late EPCs. Senescence assay and the activity of endothelial nitric oxide synthase (eNOS) were determined. Migration and tube formation assay were done to evaluate the capacity for vasculogenesis in late EPCs.RESULTS-Chronic incubation with high glucose but not mannitol (osmotic control) dose-dependently reduced the number and proliferation of early and late EPCs, respectively. High glucose enhanced EPC senescence and impaired the migration and tube formation of late EPCs. High glucose also decreased eNOS, FoxO1, and Akt phosphorylation and bioavailable nitric oxide (NO) in both EPCs. The effects of high glucose could be ameliorated by coincubation with NO donor sodium nitroprusside or p38 mitogen-activated protein kinase inhibitor and deteriorated by eNOS inhibitor or PI3K (phosphatidylinositol 3Ј-kinase) inhibitor. Antioxidants including vitamin C, N-acetylcysteine-and polyethylene glycol (PEG)-conjugated superoxide dismutase, and PEG-catalase had no effects, whereas pyrrolidine dithiocarbamate, diphenyleneiodonium, apocynin, and rotenone even deteriorated the downregulation of both EPCs. CONCLUSIONS-High

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“…Kuki et al revealed that a high glucose concentration inhibits cell proliferation and promotes the phosphorylation of p38 MAPK, and the application of p38 MAPK inhibitor restores cell proliferation, indicating that the MAPK pathway may play a significant role in the damage caused by high glucose. However, increased glucose concentrations induce dysfunction of several intracellular signal transduction cascades, including modulation of protein kinase C, generation of reactive oxygen species, and accumulation of advanced glycation end product (17).…”

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confidence: 99%

High glucose conditions suppress the function of bone marrow-derived endothelial progenitor cells via inhibition of the eNOS-caveolin-1 complex

et al. 2011

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Abstract. The present study aimed to reveal how high glucose affects rat bone marrow-derived endothelial progenitor cells in vitro. Total mononuclear cells of bone marrow were obtained, cultured in endothelial cell growth medium-2 and identified by fluorescence microscopy. Using immunofluorescence, endothelial progenitor cells were identified by expression of VEGFR-2 as well as CD133 and were further characterized as those adherent cells which were double positive by Dil-Ac-LDL uptake and FITC-UEA-1 lectin binding. The attached cells were collected and glucose was added to the culture medium at various final concentrations (11.1, 33.3 and 55.5 mmol/l). Proliferation, migration and in vitro angiogenic ability of endothelial progenitor cells were measured. The change in mRNA and protein levels of caveolin-1 and endothelial nitric oxide synthase (eNOS) were examined; in addition, nitric oxide (NO) levels in the cell medium were measured. Based on the results, with increasing glucose concentration in the medium, proliferation, migration and in vitro angiogenic capacity of the cells were reduced, whereas mRNA and protein levels of caveolin-1 gene increased gradually. The mRNA levels of the eNOS gene did not differ, but the protein expression was reduced and NO levels in the culture medium declined. In conclusion, high glucose conditions are detrimental to the function of bone marrow-derived endothelial progenitor cells in vitro, probably by damaging the eNOS-caveolin-1 complex, which results in the reduction of NO synthesis, eventually leading to the impaired function of endothelial progenitor cells.

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Hyperglycemia Accelerated Endothelial Progenitor Cell Senescence via the Activation of p38 Mitogen-Activated Protein Kinase

Cited by 116 publications

References 41 publications

Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27KIP1/p15INK4b signaling

Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27KIP1/p15INK4b signaling

High Glucose Impairs Early and Late Endothelial Progenitor Cells by Modifying Nitric Oxide–Related but Not Oxidative Stress–Mediated Mechanisms

High glucose conditions suppress the function of bone marrow-derived endothelial progenitor cells via inhibition of the eNOS-caveolin-1 complex

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