Growth kinetics rather than stress accelerate telomere shortening in cultures of human diploid fibroblasts in oxidative stress‐induced premature senescence

Dumont, Patrick; Royer, Véronique; Pascal, Thierry; Dierick, Jean‐François; Chainiaux, Florence; Frippiat, Christophe; Magalhães, João Pedro de; Eliaers, François; Remacle, José; Toussaint, Olivier

doi:10.1016/s0014-5793(01)02679-5

Cited by 42 publications

(28 citation statements)

References 13 publications

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“…These findings were also backed up similar observations using IMR90 cells expressing telomerase (Gorbunova et al 2002). Another study showed that by using multiple discontinuous subcytotoxic tert-butylhydroperoxide (t-BHP) or a single subcytotoxic H 2 O 2 treatment in WI-38 fibroblasts, a significant increase in rates of telomeres erosion was detected (Dumont et al 2001;de Magalhaes et al 2002). However, this was accounted for by the cell division of a small proportion of cells that resumed proliferation following treatment and contributed disproportionally to the increase in the PD of the culture as a whole.…”

Section: Discussionsupporting

confidence: 67%

Telomere dynamics during replicative senescence are not directly modulated by conditions of oxidative stress in IMR90 fibroblast cells

et al. 2009

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The replicative lifespan of many cell types is determined by the length of telomeres in the initiating cell population. In 20% oxygen, IMR90 cells have a shorter replicative lifespan compared to that achieved in conditions that lower the levels of oxidative stress. We sought to address the role of telomere dynamics in determining the replicative lifespan of IMR90 cells. We analysed clonal populations cultured in parallel in 3 and 20% oxygen. We observed that, at senescence, telomere length was shorter in 3% oxygen and this was proportional to the lifespan extension. We observed no detectable difference in the rate of telomere erosion in the two culture conditions, however as the cells approached senescence the growth rate of the cultures slowed with a commensurate increase in the rate of telomere erosion. We conclude that, in 20% oxygen senescence of IMR90 is telomere-independent, but telomere-dependent in 3% oxygen.

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Section: Discussionsupporting

confidence: 67%

Telomere dynamics during replicative senescence are not directly modulated by conditions of oxidative stress in IMR90 fibroblast cells

et al. 2009

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“…24 Furthermore, the view that attrition of telomeres is a marker for the oxidative stress-induced senescent cell phenotype has recently been questioned. 12,25,26 Although it has been demonstrated that proatherogenic factors inactivate telomerase in HUVECs, whereas NO activates telomerase, 19,27 it is generally true that human cells express rather low levels of telomerase activity. 23 Collectively, our findings suggest that additional mechanism(s) are operant in inducing premature endothelial cell senescence and/or that premature senescence is mechanistically distinct from replicative endothelial cell senescence.…”

Section: Discussionmentioning

confidence: 99%

Glycated Collagen I Induces Premature Senescence-Like Phenotypic Changes in Endothelial Cells

Chen

Brodsky

Goligorsky

et al. 2002

Circulation Research

148

109

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Abstract-Diabetic vasculopathy is central to the development of diverse cardiovascular, renal, retinal, and neurological complications of diabetes. We previously demonstrated that growth of endothelial cells on glycated extracellular matrix proteins (collagen and matrigel) results in a significant decrease in cell proliferation. In the present study, we show that early-passage human umbilical vein endothelial cells (HUVECs) grown on glycated collagen (GC) express hallmarks of premature cell senescence, ie, increase in the proportion of cells expressing senescence-associated ␤-galactosidase activity, apoptotic rate, and p53 and p14 AFR expression, but in contrast to replicative senescence, display neither attrition of telomeres nor decrease in telomerase activity. An increased frequency of prematurely senescent cells was similarly observed in vivo in aortae of young Zucker diabetic rats, compared with lean controls. NO production by HUVECs grown on GC was decreased, despite a 3-fold increase in eNOS expression and was associated with the increased nitrotyrosine-modified proteins. Development of premature senescence of HUVECs on GC could be prevented and reversed by treatments with the peroxynitrite scavenger, ebselen, eNOS intermediate N -hydroxy-L-arginine (NOHA), or superoxide dismutase mimetic Mn-TBAP. Concomitant with the reversal of senescence, ebselen, and NOHA each restored NO production to levels observed with HUVECs grown on unmodified collagen. Our findings indicate that diabetes mellitus in vivo and GC exposure in vitro elicit premature senescence of the vascular endothelium, a process with distinct pathogenetic mechanisms. Premature senescence of the vascular endothelium is hypothesized to be an important contributor to diabetic vasculopathy and a consequence of reduced NO availability, peroxynitrite, and/or superoxide excess. Key Words: telomerase Ⅲ nitric oxide Ⅲ superoxide Ⅲ p53 Ⅲ p14 ARF E ndothelial dysfunction is emerging as a key component in the pathophysiology of diverse cardiovascular abnormalities associated with atherosclerosis, diabetes, hypertension, and aging. 1,2 Increased incidence of apoptotic cell death has been implicated as a hallmark of endothelial dysfunction. 3-5 Molecular triggers of apoptosis in endothelial cells include oxidized LDL, TNF-␣, bacterial lipopolysaccharide, oxidative stress, peroxynitrite, turbulent fluid shear stress, and high glucose, to name a few. 6 -8 Diabetes mellitus has been shown to be associated with a gradual increase in apoptotic death of endothelial cells, 9 suggesting that some clues to vasculopathy may lie in the diabetic microenvironment.In our previous studies of endothelial cells cultured in glycated collagen (GC)-containing gels, we demonstrated a defect in branching angiogenesis, accompanied by a timedependent reduction in the rate of cell proliferation. 10 This latter finding, consistent with the possibility of developing cell senescence, 11 prompted us to explore the expression of other cellular markers of aging. Cellular aging has been ext...

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“…46 DNA strand breaks induced by oxidative stress or topoisomerase inhibitors cause poly (ADP-ribose) polymerase (PARP) hyperactivation and subsequent NAD + depletion, leading to apoptosis [10,11]. Sublethal H 2 O 2 (< 0.45 mM) treatment of human fibroblasts caused growth arrest [4] and induced a senescent-like phenotype [12][13][14]. However, the role of DNA strand breaks induced by sublethal oxidative stress in cellular senescence is unknown.…”

Section: Introductionmentioning

confidence: 99%

H2O2 Accelerates Cellular Senescence by Accumulation of Acetylated p53 via Decrease in the Function of SIRT1 by NAD+ Depletion

Furukawa

Tada‐Oikawa

Kawanishi

et al. 2007

Cell Physiol Biochem

170

113

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It has been reported that p53 acetylation, which promotes cellular senescence, can be regulated by the NAD⁺-dependent deacetylase SIRT1, the human homolog of yeast Sir2, a protein that modulates lifespan. To clarify the role of SIRT1 in cellular senescence induced by oxidative stress, we treated normal human diploid fibroblast TIG-3 cells with H₂O₂ and examined DNA cleavage, depletion of intracellular NAD⁺, expression of p21, SIRT1, and acetylated p53, cell cycle arrest, and senescence-associated β-galactosidase (SA-β-gal) activity. DNA cleavage was observed immediately in TIG-3 cells treated with H₂O₂, though no cell death was observed. NAD⁺ levels in TIG-3 cells treated with H₂O₂ were also decreased significantly. Pre-incubation with the poly (ADP-ribose) polymerase (PARP) inhibitor resulted in preservation of intracellular NAD⁺ levels. The amount of acetylated p53 was increased in TIG-3 cells at 4h after H₂O₂ treatment, while there was little to no decrease in SIRT1 protein expression. The expression level of p21 was increased at 12h and continued to increase for up to 24h. Additionally, exposure of TIG-3 cells to H₂O₂ induced cell cycle arrest at 24h and increased SA-β-gal activity at 48h. This pathway likely plays an important role in the acceleration of cellular senescence by oxidative stress.

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Growth kinetics rather than stress accelerate telomere shortening in cultures of human diploid fibroblasts in oxidative stress‐induced premature senescence

Cited by 42 publications

References 13 publications

Telomere dynamics during replicative senescence are not directly modulated by conditions of oxidative stress in IMR90 fibroblast cells

Telomere dynamics during replicative senescence are not directly modulated by conditions of oxidative stress in IMR90 fibroblast cells

Glycated Collagen I Induces Premature Senescence-Like Phenotypic Changes in Endothelial Cells

H<sub>2</sub>O<sub>2</sub> Accelerates Cellular Senescence by Accumulation of Acetylated p53 via Decrease in the Function of SIRT1 by NAD<sup>+</sup> Depletion

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