FoxO3a suppresses the senescence of cardiac microvascular endothelial cells by regulating the ROS-mediated cell cycle

Qi, Xu; Chen, Zhuo Ying; Xia, Jing; Zheng, Li; Zhao, Hui; Pi, Long Quan; Park, Kyu Sang; Kim, Soo Ki; Lee, Kyu-Jae; Cai, Dongqing

doi:10.1016/j.yjmcc.2015.01.022

Cited by 31 publications

(29 citation statements)

References 34 publications

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“…Apart from the regulation of the level of P27 by SKP2, P27 is also regulated by the FoxO3a protein at the transcriptional level [14]. Also, FoxO3a could be regulated by AKT and 14-3-3 protein [21].…”

Section: Resultsmentioning

confidence: 99%

“…The data shows that FoxO3a participates in the process of many kinds of cell senescence. Xu-Feng et al found that FoxO3a can inhibit the senescence of cardiovascular endothelial cells by regulating the cell cycle mediated by ROS [14]. Similarly, in the experiment of Kyoung Kim H et al, FoxO3a also exhibited an inhibition effect on human dermal fibroblast senescence.…”

Section: Discussionmentioning

confidence: 98%

“…In addition to the regulation of the post transcriptional level of P27 by SKP2, P27 is also regulated by the FoxO3a protein at the transcriptional level [14]. The data shows that FoxO3a participates in the process of many kinds of cell senescence.…”

Section: Discussionmentioning

confidence: 99%

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Soluble Egg Antigens of Schistosoma japonicum Induce Senescence of Activated Hepatic Stellate Cells by Activation of the FoxO3a/SKP2/P27 Pathway

et al. 2016

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BackgroundLiver fibrosis was viewed as a reversible process. The activation of hepatic stellate cells (HSCs) is a key event in the process of liver fibrosis. The induction of senescence of HSCs would accelerate the clearance of the activated HSCs. Previously, we demonstrated that soluble egg antigens (SEA) of Schistosoma japonicum promoted the senescence of HSCs via STAT3/P53/P21 pathway. In this paper, our study was aimed to explore whether there are other signaling pathways in the process of SEA-induced HSCs aging and the underlying effect of SKP2/P27 signal on senescent HSCs.Methodology/Principal findingsHuman hepatic stellate cell line, LX-2 cells, were cultured and stimulated with SEA. Western blot and cellular immunofluorescence analysis were performed to determine the expression of senescence-associated protein, such as P27, SKP2 and FoxO3a. Besides, RNA interfering was applied to knockdown the expression of related protein. The senescence of HSCs was determined by senescence-associated β-gal staining. We found that SEA increased the expression of P27 protein, whereas it inhibited the expression of SKP2 and FoxO3a. Knockdown of P27 as well as overexpression of SKP2 both suppressed the SEA-induced senescence of HSCs. In addition, the nuclear translocation of FoxO3a from the nucleus to the cytoplasm was induced by SEA stimulation.Conclusions/SignificanceThe present study demonstrates that SEA promotes HSCs senescence through the FoxO3a/SKP2/P27 pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

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Soluble Egg Antigens of Schistosoma japonicum Induce Senescence of Activated Hepatic Stellate Cells by Activation of the FoxO3a/SKP2/P27 Pathway

et al. 2016

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“…To construct the lentiviral vector expressing an shRNA targeting mouse TLR9, an shRNA expression cassette (7SK‐shRNA‐TLR9) was isolated from the psiRNA‐TLR9 plasmid (InvivoGen, San Diego, CA) using ClaI and XbaI double digestion, which was inserted into the pLOXCMV‐E/P lentiviral vector (Qi et al, ) to replace the CMV promoter by ClaI and SpeI ( SpeI and XbaI has the same cohesive terminus) double digestion. The pLOXshRNA‐TLR9 lentiviral vector was then constructed.…”

Section: Methodsmentioning

confidence: 99%

CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis

Zhou

Jiang³

et al. 2017

Journal Cellular Physiology

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Unmethylated CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) ligand, has been shown to protect against myocardial ischemia/reperfusion injury. However, the potential effects of CpG-ODN on myocardial infarction (MI) induced by persistent ischemia remains unclear. Here, we investigated whether and how CpG-ODN preconditioning protects against MI in mice. C57BL/6 mice were treated with CpG-ODN by i.p. injection 2 hr prior to MI induction, and cardiac function, and histology were analyzed 2 weeks after MI. Both 1826-CpG and KSK-CpG preconditioning significantly improved the left ventricular (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS) when compared with non-CpG controls. Histological analysis further confirmed the cardioprotection of CpG-ODN preconditioning. In vitro studies further demonstrated that CpG-ODN preconditioning increases cardiomyocyte survival under hypoxic/ischemic conditions by enhancing stress tolerance through TLR9-mediated inhibition of the SERCA2/ATP and activation of AMPK pathways. Moreover, CpG-ODN preconditioning significantly increased angiogenesis in the infarcted myocardium compared with non-CpG. However, persistent TLR9 activation mediated by lentiviral infection failed to improve cardiac function after MI. Although CpG-ODN preconditioning increased angiogenesis in vitro, both the persistent stimulation of CpG-ODN and stable overexpression of TLR9 suppressed the tube formation of cardiac microvascular endothelial cells. CpG-ODN preconditioning significantly protects cardiac function against MI by suppressing the energy metabolism of cardiomyocytes and promoting angiogenesis. Our data also indicate that CpG-ODN preconditioning may be useful in MI therapy.

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“…Downregulation of FOXO3A gene and protein expression by siRNA [38] and inhibition of FOXO3A by overexpression of Akt [39] have been shown to accelerate senescence in HDFs. In addition, knockout of FOXO3A promoted replicative senescence in mouse embryonic fibroblast [40] and inactive form of FOXO3A was increased in replicative senescent rat cardiac microvascular endothelial cells [41]. In this study, however, FOXO3A gene expression remained unchanged among 3 PD groups, suggesting that the role of FOXO3A during replicative senescence might depend on types of cellular models studied.…”

Section: Discussionmentioning

confidence: 73%

Piper betle L. Modulates Senescence-Associated Genes Expression in Replicative Senescent Human Diploid Fibroblasts

Durani

Khor

Tan

et al. 2017

BioMed Research International

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Piper betle (PB) is a traditional medicine that is widely used to treat different diseases around Asian region. The leaf extracts contain various bioactive compounds, which were reported to have antidiabetic, antibacterial, anti-inflammatory, antioxidant, and anticancer effects. In this study, the effect of PB aqueous extracts on replicative senescent human diploid fibroblasts (HDFs) was investigated by determining the expressions of senescence-associated genes using quantitative PCR. Our results showed that PB extracts at 0.4 mg/ml can improve cell proliferation of young (143%), presenescent (127.3%), and senescent (157.3%) HDFs. Increased expressions of PRDX6, TP53, CDKN2A, PAK2, and MAPK14 were observed in senescent HDFs compared to young and/or presenescent HDFs. Treatment with PB extracts modulates the transcriptional profile changes in senescent HDFs. By contrast, expressions of SOD1 increased, whereas GPX1, PRDX6, TP53, CDKN2A, PAK2, and MAPK14 were decreased in PB-treated senescent HDFs compared to untreated senescent HDFs. In conclusion, this study indicates the modulation of PB extracts on senescence-associated genes expression of replicative senescent HDFs. Further studies warrant determining the mechanism of PB in modulating replicative senescence of HDFs through these signaling pathways.

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FoxO3a suppresses the senescence of cardiac microvascular endothelial cells by regulating the ROS-mediated cell cycle

Cited by 31 publications

References 34 publications

Soluble Egg Antigens of Schistosoma japonicum Induce Senescence of Activated Hepatic Stellate Cells by Activation of the FoxO3a/SKP2/P27 Pathway

Soluble Egg Antigens of Schistosoma japonicum Induce Senescence of Activated Hepatic Stellate Cells by Activation of the FoxO3a/SKP2/P27 Pathway

CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis

Piper betle L. Modulates Senescence-Associated Genes Expression in Replicative Senescent Human Diploid Fibroblasts

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