Role of endonuclease G in senescence-associated cell death of human endothelial cells

Diener, Thomas; Neuhaus, Michael; Kozieł, Rafał; Mičutková, Lucia; Jansen‐Dürr, Pidder

doi:10.1016/j.exger.2010.03.002

Cited by 23 publications

(12 citation statements)

References 49 publications

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“…In addition, multiple CMP-induced genomic changes were linked to protracted stress, energy and calcium regulation as well as neurodegenerative processes, e.g. DNM1L [65], [66], SPTLC1 [67], [68]) and ENDOG [69]. Relatively novel CMP-controlled factors linked to neurodegeneration were uncovered, e.g.…”

Section: Discussionmentioning

confidence: 99%

Minimal Peroxide Exposure of Neuronal Cells Induces Multifaceted Adaptive Responses

et al. 2010

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Oxidative exposure of cells occurs naturally and may be associated with cellular damage and dysfunction. Protracted low level oxidative exposure can induce accumulated cell disruption, affecting multiple cellular functions. Accumulated oxidative exposure has also been proposed as one of the potential hallmarks of the physiological/pathophysiological aging process. We investigated the multifactorial effects of long-term minimal peroxide exposure upon SH-SY5Y neural cells to understand how they respond to the continued presence of oxidative stressors. We show that minimal protracted oxidative stresses induce complex molecular and physiological alterations in cell functionality. Upon chronic exposure to minimal doses of hydrogen peroxide, SH-SY5Y cells displayed a multifactorial response to the stressor. To fully appreciate the peroxide-mediated cellular effects, we assessed these adaptive effects at the genomic, proteomic and cellular signal processing level. Combined analyses of these multiple levels of investigation revealed a complex cellular adaptive response to the protracted peroxide exposure. This adaptive response involved changes in cytoskeletal structure, energy metabolic shifts towards glycolysis and selective alterations in transmembrane receptor activity. Our analyses of the global responses to chronic stressor exposure, at multiple biological levels, revealed a viable neural phenotype in-part reminiscent of aged or damaged neural tissue. Our paradigm indicates how cellular physiology can subtly change in different contexts and potentially aid the appreciation of stress response adaptations.

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Section: Discussionmentioning

confidence: 99%

Minimal Peroxide Exposure of Neuronal Cells Induces Multifaceted Adaptive Responses

et al. 2010

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“…This affects mitochondrial membrane integrity and triggers cytochrome c release35 to cause the activation of caspase‐9 and subsequently leads to the activation of effector caspase‐336 for causing apoptosis. In some cases, the mitochondrial dysfunction of cells will release apoptosis‐inducing factor (AIF)37 and endonuclease G (Endo G)38 to induce apoptosis directly.…”

mentioning

confidence: 99%

Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC)‐mediated generation of reactive oxygen species causes cell cycle arrest and induces apoptosis via activation of caspase‐3, mitochondria dysfunction and nitric oxide (NO) in human osteogenic sarcoma U‐2 OS cells

Huang²,

Yang

et al. 2011

Journal Orthopaedic Research

101

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Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), a member of the isothiocyanate family, have been shown to exhibit antineoplastic ability against many human cancer cells. In this study, we found that exposure of human osteogenic sarcoma U-2 OS cells to BITC and PEITC led to induce morphological changes and to decrease the percentage of viable cells in a time-and dose-dependent manner. BITC and PEITC induced cell cycle arrest at G2/M phase at 48 h treatment and inhibited the levels of cell cycle regulatory proteins such as cyclin A and B1 in U-2 OS cells but promoted the level of Chk1 and p53 that led to G2/M arrest. BITC and PEITC induced a marked increase in apoptosis (DNA fragmentation) and poly(ADP-ribose)polymerase (PARP) cleavage, which was associated with mitochondrial dysfunction and the activation of caspase-9 and -3. BITC and PEITC also promoted the ROS production in U-2 OS cells and the N-acetylcysteine (NAC, an antoxidant agent) was pretreated and then treated with both compounds which led to decrease the levels of ROS and increase the cell viability. Interestingly, BITC and PEITC promoted the levels of NO production and increased the iNOS enzyme. Confocal laser microscope also demonstrated that BITC and PEITC promoted the release of cytochrome c and AIF, suggesting that both compounds induced apoptosis through ROS, caspase-3 and mitochondrial, and NO signaling pathways. Taken together, these molecular alterations and signaling pathways offer an insight into BITC and PEITC-caused growth inhibition, G2/M arrest, and apoptotic death of U-2 OS cells. ß

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“…To the best of our knowledge, this is the first report that suggests the causative role of EndoG in mitotic endothelial cell death induced by cLDL or any other modified LDL. Interestingly, Diener and coauthors (17) recently suggested that under normal physiological conditions, EndoG protects endothelial cells from apoptosis and, at the same time, potentiates necrosis. This contradiction with our results can be perhaps explained by the difference in the cell death mechanisms between normal conditions and conditions resulting from cLDL toxicity.…”

Section: Discussionmentioning

confidence: 97%

Endonuclease G mediates endothelial cell death induced by carbamylated LDL

Apostolov¹,

Ray²,

Alobuia³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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End-stage kidney disease is a terminal stage of chronic kidney disease, which is associated with a high incidence of cardiovascular disease. Cardiovascular disease frequently results from endothelial injury caused by carbamylated LDL (cLDL), the product of LDL modification by urea-derived cyanate. Our previous data suggested that cLDL induces mitogen-activated protein kinase-dependent mitotic DNA fragmentation and cell death. However, the mechanism of this pathway is unknown. The current study demonstrated that cLDL-induced endothelial mitotic cell death is independent of caspase-3. The expression of endonuclease G (EndoG), the nuclease implicated in caspase-independent DNA fragmentation, was significantly increased in response to cLDL exposure to the cells. The inhibition of EndoG by RNAi protected cLDL-induced DNA fragmentation, whereas the overexpression of EndoG induced more DNA fragmentation in endothelial cells. Ex vivo experiments with primary endothelial cells isolated from wild-type (WT) and EndoG knockout (KO) mice demonstrated that EndoG KO cells are partially protected against cLDL toxicity compared with WT cells. To determine cLDL toxicity in vivo, we administered cLDL or native LDL (nLDL) intravenously to the WT and EndoG KO mice and then measured floating endothelial cells in blood using flow cytometry. The results showed an increased number of floating endothelial cells after cLDL versus nLDL injection in WT mice but not in EndoG KO mice. Finally, the inhibitors of MEK-ERK1/2 and JNK-c-jun pathways decreased cLDL-induced EndoG overexpression and DNA fragmentation. In summary, our data suggest that cLDL-induced endothelial toxicity is caspase independent and results from EndoG-dependent DNA fragmentation.

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Role of endonuclease G in senescence-associated cell death of human endothelial cells

Cited by 23 publications

References 49 publications

Minimal Peroxide Exposure of Neuronal Cells Induces Multifaceted Adaptive Responses

Minimal Peroxide Exposure of Neuronal Cells Induces Multifaceted Adaptive Responses

Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC)‐mediated generation of reactive oxygen species causes cell cycle arrest and induces apoptosis via activation of caspase‐3, mitochondria dysfunction and nitric oxide (NO) in human osteogenic sarcoma U‐2 OS cells

Endonuclease G mediates endothelial cell death induced by carbamylated LDL

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